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Left Ventricular Conduction Delays and Relation to QRS Configuration in Patients With Left Ventricular Dysfunction
Left Ventricular Conduction Delays and Relation to QRS Configuration in Patients With Left Ventricular Dysfunction Niraj Varma, MD, PhD* Left ventricular activation delay (LVAT) >100 ms may determine response to cardiac resynchronization therapy, but its prevalence and relation to QRS configuration are unknown. QRS duration and LVAT in control subjects (n ⴝ 30) were compared with those in patients with heart failure (HF; LV ejection fraction 23 ⴞ 8%, n ⴝ 120) with a QRS duration <120 ms (NQRSHF, n ⴝ 35) or >120 ms (left bundle branch block [LBBBHF], n ⴝ 54; right bundle branch block [RBBBHF], n ⴝ 31). LVAT was estimated by interval from QRS onset to basal inferolateral LV depolarization. In controls, QRS duration was 82 ⴞ 13 ms and LVAT was 55 ⴞ 18 ms. LVAT was always <100 ms. In patients with NQRSHF, QRS duration (104 ⴞ 10 ms) and LVAT (82 ⴞ 22 ms) were prolonged versus controls (p <0.001). LVAT exceeded 100 ms in 8 of 35 patients. In patients with LBBBHF, QRS duration (161 ⴞ 29 ms) and LVAT (136 ⴞ 33 ms) were prolonged compared with controls and patients with NQRSHF (p <0.001). LVAT exceeded 100 ms in 47 of 54 patients. In patients with RBBBHF, QRS duration did not differ from that in patients with LBBBHF, but LVAT (100 ⴞ 24 ms) was shorter (p <0.001). In 17 of 31 patients with RBBBHF LVAT was <100 ms (82 ⴞ 12), similar to those with NQRSHF (p ⴝ NS), indicating no LV conduction delay. However, in 7 of 31, LVAT (135 ⴞ 13 ms) was similar to that in patients with LBBBHF (p ⴝ NS). LVAT correlation with QRS duration varied (control p ⴝ 0.004, NQRSHF p ⴝ 0.15, RBBBHF p ⴝ 0.01, LBBBHF p <0.001). In conclusion, LV conduction delays in patients with HF varied with QRS configuration and duration, exceeding 100 ms in only 23% of patients with narrow QRS configuration and 45% with RBBBHF compared with 87% with LBBBHF. Fewer than 25% of patients with RBBBHF demonstrated delays equivalent to those in patients with LBBBHF. These variations may affect efficacy to cardiac resynchronization therapy. © 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;103:1578 –1585) Cardiac resynchronization therapy improves survival in heart failure (HF).1 The premise of cardiac resynchronization therapy is that patients exhibiting prolonged QRS duration have inferolateral left ventricular (LV) conduction delay causing mechanical dysfunction, remediable by paced pre-excitation of this terminally activated region. Mechanical measurements derived echocardiographically have been ineffective for identifying responders.2,3 Prolonged QRS duration, therefore, remains the mainstay of selection, although imperfect. Thus, “prolongation” has been variously defined as ⬎150, ⬎130 or ⱖ120 ms in different studies4 – 6 and cardiac resynchronization therapeutic effect is controversial when prolongation is due to right bundle branch block (RBBB).7–9 However, QRS configuration is a surface depiction of biventricular activation and may not specifically report inferolateral LV conduction delay, a potential determinant of cardiac resynchronization therapeutic effect. For example, LV pacing of already early activated regions is unlikely to be helpful but, in contrast, may be beneficial when delays exceed approximately 100 ms.10,11 Similar QRS configurations may not indicate similar LV conduction Cardiac Electrophysiology, Cleveland Clinic, Cleveland, Ohio. Manuscript received December 16, 2008; revised manuscript received and accepted January 31, 2009. *Corresponding author: Tel: 216-444-2142; fax: 206-445-6161. E-mail address: [email protected] (N. Varma). 0002-9149/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.01.379
delays. The ability to derive LV conduction delays from the surface electrocardiogram is therefore a critical element to the evaluation of the role of QRS duration as a selection criterion and its acknowledged limitations. In this study, I hypothesized that terminal inferolateral LV activation during intrinsic conduction in patients with HF would vary in absolute terms and differ in relation to QRS width and configuration. Methods The method has been previously described.12 Briefly, the study population consisted of consecutive patients undergoing routine electrophysiologic study and/or cardiac resynchronization therapy. The control group (n ⫽ 30) had normal LV function and normal QRS configuration. Patients with LV dysfunction (HF, LV ejection fraction ⬍40%) were categorized into groups according to baseline conduction pattern: those with normal QRS duration (⬍120 ms) and configuration (NQRSHF, n ⫽ 35), those with RBBB (RBBBHF, n ⫽ 31), and those with left bundle branch block (LBBBHF, n ⫽ 54). When QRS duration was ⱖ120 ms, LBBB was diagnosed by an RsR= complex in leads V6 and rS or QS deflection in lead V1 or V2 and RBBB by a dominant terminal R wave in lead V1 (triphasic complex rSR, qR, or R). Patients were excluded if they had atrioventricular block and no intrinsic conduction, or when an LV electrogram was not clearly inscribed during coronary sinus mapping. All www.AJConline.org
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Figure 1. (Left) Schematic of terminal LV depolarization (LVAT) in the epicardium of the inferolateral base of the left ventricle (LV) (shaded) recorded by electrode mapping along the atrioventricular ring through the coronary sinus (CS). (Right) Representative tracing from a control patient with a structurally normal heart and normal QRS configuration and duration. Bipolar electrograms displayed are recorded from electrode catheters sited at the proximal and distal coronary sinus (CS px, CS ds), His bundle (His), and right ventricular apex (RVA). Table 1 Patient demographics
Control NQRSHF RBBBHF LBBBHF
Patients
Age (yrs)
Men
Patients With AF
Patients With AA Rx
Patients With CAD/NICM
LVEF (%)
30 35 31 54
61 ⫾ 19 64 ⫾ 11 70 ⫾ 13 66 ⫾ 16
18 (60%) 28 (80%) 24 (77%) 45 (83%)
0 (0%) 5 (14%) 6 (19%) 11 (20%)
0 (0%) 4 (11%) 6 (19%) 8 (15%)
0/0 20 (57%)/15(43%) 23 (74%)/8 (26%) 30 (56%)/24 (44%)
Normal 25 ⫾ 8 24 ⫾ 8 22 ⫾ 8*
* p ⫽ 0.043 versus NQRSHF. AA Rx ⫽ antiarrhythmic drug therapy with amiodarone; AF ⫽ atrial fibrillation; CAD ⫽ coronary artery disease; LVEF ⫽ LV ejection fraction; NICM ⫽ nonischemic cardiomyopathy. Table 2 QRS duration and inferolateral left ventricular activation time during intrinsic conduction Group Control NQRSHF RBBBHF LBBBHF
QRSd (ms)
LVAT (ms)
QRSd ⫺ LVAT (ms)
82 ⫾ 13 (65–110) 104 ⫾ 10* (80–120) 165 ⫾ 18* (132–206) 161 ⫾ 29* (121–233)
55 ⫾ 18 (30–95) 82 ⫾ 22* (40–135) 100 ⫾ 24* (60–155) 136 ⫾ 33* (67–200)
27 ⫾ 16 22 ⫾ 21 65 ⫾ 23* 25 ⫾ 16
Values are means ⫾ SDs (ranges). * p ⬍0.001 versus control. QRSd ⫽ QRS duration; LVAT ⫽ left ventricular activation time.
patients provided informed written consent, conforming to institutional guidelines. Electrograms were recorded from a multipolar electrode catheter (at electrophysiologic study or from the coronary sinus sheath for LV lead implantation) positioned in the coronary sinus so the distal electrode marked the inferolateral position (according to the 17-segment nomenclature13) on the mitral ring (Figure 1). Catheter position was verified with fluoroscopy in left and right oblique views. Surface electrocardiographic leads and intracardiac signals (bipolar, filtered 30 to 500 Hz) were simultaneously recorded and stored digitally on optical disk (Prucka Engineering, Houston, Texas). Measurements
were made with electronic callipers at screen speeds of 200 to 400 mm/s. All activation times were referenced to earliest onset of the QRS complex in any lead. QRS duration was measured manually from the beginning of the earliest QRS complex in any lead to the end in any lead using simultaneously displayed electrocardiographic signals. Inferolateral LV activation time (LVAT, milliseconds) was assessed during coronary sinus electrode mapping, measured as the interval between QRS onset (earliest in any surface lead) and the intrinsicoid of the inscribed LV electrogram (i.e., the point at which the largest rapid deflection crossed the baseline). An LVAT value ⬎100 ms was considered significant. The relation of inferolateral LV activation to terminal ventricular depolarization was indexed by the difference between the end of the QRS complex and LVAT (QRS duration minus LVAT). Data are reported as mean ⫾ SD. Comparisons between groups were done by unpaired t test (SPSS 13, SPSS, Inc., Chicago, Illinois). A p value ⬍0.05 was considered statistically significant. Simple linear regression was used to study the association between LVAT and QRS duration. Results Demographics of study groups are presented in Table 1 and their data in Table 2. In HF (n ⫽ 120, LV ejection fraction 23 ⫾ 8%), groups (NQRSHF, LBBBHF, and
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Figure 2. (Top) Representative surface electrocardiographic recordings and intracardiac electrograms during intrinsic conduction illustrating mean LVAT values in each HF group. LVAT in the LBBBHF group exceeded that in the RBBBHF group in these examples, which were greater than those in the NQRSHF group. (Bottom) LVAT exceeded 100 ms infrequently (23%) in the NQRSHF group but in most patients (87%) with LBBBHF. Abbreviations as in Figure 1.
RBBBHF) were matched for age, pathology, incidence of atrial fibrillation, and use of amiodarone. Figure 2 shows representative electrograms and LVAT frequency distributions and Figure 3 displays comparisons between groups. Intrinsic conduction in the control group resulted in a QRS duration of 82 ⫾ 13 ms. Inferolateral LV activation (LVAT) occurred 55 ⫾ 18 ms after QRS onset, 27 ⫾ 16 ms before the end of the QRS complex. Increasing QRS duration in different patients correlated with more prolonged LVAT (r ⫽ 0.52, p ⫽ 0.004; Figure 4). LVAT did not exceed 100 ms in any patient. In the NQRSHF group, QRS duration and LVAT were 22 ⫾ 3 and 27 ⫾ 5 ms longer, respectively, compared with the control group, despite QRS configuration being normal in the 2 groups (QRS duration 104 ⫾ 10 vs 82 ⫾ 13 ms, p ⬍0.001; LVAT 82 ⫾ 22 vs 55 ⫾ 18 ms, p ⬍0.001). LVAT occurred 22 ⫾ 21 ms before QRS termination, which was not different from the control group (p ⫽ NS). However, LVAT did not correlate with QRS duration in the NQRSHF group (r ⫽ 0.25, p ⫽ 0.15; Figure 4). QRS duration and LVAT did not differ in patients with ischemic and nonischemic cardiomyopathy (QRS duration 106 ⫾ 10 vs
101 ⫾ 10 ms, LVAT 79 ⫾ 21 vs 86 ⫾ 22 ms, respectively, p ⫽ NS). LVAT exceeded 100 ms in 8 of 35 patients (23%). In the LBBBHF group, QRS duration (161 ⫾ 29 ms) and LVAT (136 ⫾ 33 ms) during intrinsic conduction were prolonged compared with the control and NQRSHF groups (p ⬍0.001). LVAT occurred 25 ⫾ 16 ms before QRS termination, which was not different from the control or NQRSHF group (p ⫽ NS), indicating that the inferolateral LV region participated similarly in terminal ventricular depolarization in these groups. Increasing QRS duration in the LBBBHF group correlated strongly with more prolonged LVAT (r ⫽ 0.88, p ⬍0.001; Figure 4). LVAT/QRS ratio was 84 ⫾ 11%. LVAT exceeded 100 ms in 47 of 54 patients (87%). LVAT in the remaining 7 patients (QRS duration 130 ⫾ 8 ms) was 80 ⫾ 14 ms, similar to the NQRSHF group (p ⫽ NS). QRS duration and LVAT did not differ in patients with ischemic and nonischemic cardiomyopathy (QRS duration 161 ⫾ 30 vs 161 ⫾ 27 ms, LVAT 126 ⫾ 35 vs 138 ⫾ 30 ms, respectively, p ⫽ NS). The LBBBHF group was subdivided into 3 groups according to QRS duration ranges of 120 to 130, 131 to 150, and ⬎151 ms (Figure 5). When QRS duration was 120 to
Heart Failure/LV Conduction Delays in Heart Failure
*
200
*
LVAT (ms)
150
*
100
50
0 CONTROL
NQRSHF
RBBBHF
LBBBHF
Figure 3. LVAT data are presented in Tukey box plots to illustrate degree of data dispersion, which was minimal in the control group and maximal in the LBBBHF group. Delays were greater in all HF groups versus the control group (p ⬍0.001). Delays in the LBBBHF group exceeded those in the RBBBHF group and delays in these 2 groups were greater than that in the NQRSHF group. Compared with an LVAT equal to 100 ms (dashed line), LVATs in all control patients were shorter. In the NQRSHF group, the interquartile range (box length) was ⬍100 ms contrasting with the LBBBHF group, where the range was ⬎100 ms. In the RBBBHF group, the box crossed this value and the median (cross bar on box) equalled 100 ms (*p ⬍0.001 vs control and between groups).
130 ms (9 of 54 patients, 17%), QRS duration was 126 ⫾ 4 ms and LVAT was 98 ⫾ 19 ms (range 67 to 125). LVAT exceeded 100 ms in 4 of 9 patients (44%). LVAT was 16 ⫾ 7 ms longer compared with the NQRSHF group (98 ⫾ 19 vs 82 ⫾ 22 ms, p ⫽ 0.052). When QRS duration was 131 to 150 ms (17 of 54 patients, 31%), QRS duration was 141 ⫾ 6 ms and LVAT was 117 ⫾ 21 ms (range 60 to 150). LVAT exceeded 100 ms in 15 of 17 patients (88%). In patients with LBBBHF in whom QRS duration exceeded 151 ms (28 of 54 patients, 52%), QRS duration was 184 ⫾ 19 ms and LVAT was 160 ⫾ 22 ms (range 106 to 200). LVAT/QRS duration ratio was 87 ⫾ 8%. LVAT exceeded 100 ms in 28 of 28 patients (100%). In the RBBBHF group, QRS duration during intrinsic conduction was wider compared with the control and NQRSHF groups (p ⬍0.001). LVAT was 100 ⫾ 24 ms, i.e., prolonged compared with the control or NQRSHF group (p ⬍0.001), indicating the presence of significant LV conduction delay. Compared with the LBBBHF group, however, QRS duration did not differ (RBBBHF 165 ⫾ 18 ms vs LBBBHF 161 ⫾ 29 ms, p ⫽ NS) and LV conduction delay was less (RBBBHF 100 ⫾ 24 ms vs LBBBHF 136 ⫾ 33 ms, p ⬍0.001). QRS duration ⬎150 ms was recorded in 27 of 31 patients with RBBBHF and LVAT exceeded 100 ms in 14 of 27 (52%). QRS width correlated with inferolateral LV activation delay but not as strongly compared with the LBBBHF group (r ⫽ 0.44, p ⫽ 0.02; Figure 4). Inferolateral LV depolarization in the RBBBHF group occurred 65 ⫾ 23 ms before QRS termination, i.e., LV activation, although
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delayed in absolute terms, was completed earlier relative to overall ventricular depolarization compared with other groups (p ⬍0.001). LV activation delay varied widely in the RBBBHF group (median 100 ms, range 60 to 155; Figures 2 and 3). Although QRS duration did not differ, LVAT in patients with nonischemic cardiomyopathy was significantly longer than in those with ischemic disease (QRS duration 166 ⫾ 14 vs 164 ⫾ 19 ms, p ⫽ NS; LVAT 125 ⫾ 19 vs 97 ⫾ 28 ms, respectively, p ⫽ 0.016). Overall, LVAT was ⬍100 ms in 17 of 31 patients (55%, 82 ⫾ 12 ms) and these did not differ from the NQRSHF group (p ⫽ NS), indicating that inferolateral LV depolarization was not delayed. However, in 14 of 31 patients (45%) with RBBBHF, LVAT was ⱖ100 ms (mean 121 ⫾ 18). This group was characterized by wider QRS duration (172 ⫾ 14 vs 158 ⫾ 18 ms, p ⬍0.03) and lower LV ejection fraction (21 ⫾ 6% vs 26 ⫾ 9%, p ⬍0.02). In 7 patients (23% of RBBBHF group), LVAT exceeded 120 ms and did not differ from the LBBBHF group (135 ⫾ 13 vs 136 ⫾ 33 ms, p ⫽ NS). These patients (compared with those with RBBBHF without concomitant LV conduction delay) had poorer LV function (LV ejection fraction 18 ⫾ 5%, p ⬍0.03) and more prolonged QRS durations (175 ⫾ 16 ms, p ⬍0.05; Figure 6). Discussion This study is the first to quantify in a large population the relation among QRS width, QRS morphology, and LVAT. Incidence of significant LV activation delays (⬎100 ms) varied in patients with HF separated according to QRS configuration, occurring most frequently with LBBB, at an intermediate rate (45%) in RBBB, and in only 23% when QRS was normal. No control patient demonstrated LV conduction delays ⬎100 ms. QRS duration correlated strongly with late inferolateral LV activation in LBBBHF. When QRS duration was ⬎150 ms, LVAT exceeded 100 ms in 100% of patients with LBBBHF but in only 52% of patients with RBBBHF. Cardiac resynchronization therapy is based on the premise that paced pre-excitation of late depolarized and contracting LV regions in patients with LBBB reverses deleterious mechanical effects.14 Current echocardiographic measurements have not been effective discriminators of potential responders.2,3 In contrast, the prognostic import of LV conduction delays is indicated by the observations that a wide QRS configuration generated by LBBB or right ventricular apical pacing, which delay inferolateral LV electrical activation, increase mortality, whereas LV paced preexcitation of this same region with cardiac resynchronization therapy improves survival.1,15,16 Implicitly, pacing a LV region that is not subject to delayed activation may not confer benefit. Conduction delay triggers regional molecular and metabolic remodeling.17 LBBB occurring in structurally normal hearts delayed inferolateral LV depolarization to 116 ⫾ 10 ms (range 87 to 135, median 115).12 Possibly a longer delay may promote greater adverse remodeling and may explain induction of cardiomyopathy in only some patients by this conduction lesion, readily reversible with cardiac resynchronization therapy.18 During right ventricular apical pacing, longer QRS duration, which in
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Figure 4. Correlations between LVATs and QRS width show the strongest correlation for LBBBHF. There was no significant correlation for NQRSHF.
this condition is tightly linked to inferolateral LV conduction delay,12 was associated with greater deleterious effect.19 The clinical value of this delay becomes evident during cardiac resynchronization therapy. Greater delay in patients with LBBB correlated with better cardiac resynchronization therapeutic response.10 LV leads placed inferolaterally, the site of terminal LV activation, improved response.20 A delay recorded at the LV lead location exceeding 90 to 115 ms appeared to be significant in models21 and correlated with cardiac resynchronization therapeutic effect in clinical studies,10,11,20 and, hence, a cutpoint of 100 ms was used in this study. In support of this threshold, this value was observed to exceed 2 SDs from the mean in the control group. Terminal LV depolarization may not be reported by estimation of LV activation delay to LV electrode sites due to positional variability. For example, anteriorly placed leads report earlier activation in absolute timings and relative to QRS forces.10,20 This limitation was avoided in the present study by consistently assessing a single LV region
involved in terminal activation. The method used a fundamental LV characteristic, i.e., depolarization proceeds from the endocardium to the epicardium and from the apex to the base. Terminal LV depolarization occurs in the inferolateral base adjacent to the atrioventricular sulcus. Several studies using different techniques including intraoperative epicardial mapping, endocardial catheter or electroanatomical mapping,22–24 epicardial imaging,25 or isolated heart studies have demonstrated that the inferolateral area is depolarized last during intrinsic conduction in normal subjects and during LBBB26 and only exceptionally anterolaterally. This pattern of LV activation was retained during RBBB.27 The epicardium of the inferolateral base of the left ventricle may be conveniently mapped by LV electrograms recorded through the coronary sinus. The present results demonstrated that depolarization (LVAT) occurred approximately 25 ms before final QRS inscription in the control, NQRSHF, and LBBBHF groups (because right ventricular delays determine final QRS forces in RBBBHF, terminal LV activation occurred earlier during the QRS complex despite ab-
Heart Failure/LV Conduction Delays in Heart Failure
200
*
p < 0.03 p = 0.052
LVAT (ms)
150
100
50
0
NQRSHF
120-130 ms LBBBHF
131-150 ms LBBBHF
151+ ms LBBBHF
Figure 5. Comparison of LVATs in the NQRSHF and LBBBHF groups divided into 3 subgroups according to QRS durations of 120 to 130, 131 to 150, and ⬎151 ms. Data are presented in Tukey box plots to illustrate degree of data dispersion. The interquartile range (box length) was ⬎100 ms (dashed line) only when QRS duration exceeded 130 ms (*p ⬍0.001 vs other groups).
solute LV activation being delayed). In further support of this measurement reflecting terminal LV depolarization, absolute LVAT values in this study reported similar or later terminal LVATs compared with previously reported endocardial mapping. For example, an LVAT of 55 ⫾ 18 ms in the control group was similar to 58 ⫾ 6 ms reported by Rodriguez et al.23 In patients with RBBBHF with poorer LV function, LVAT was 135 ⫾ 13 ms compared with 135 ⫾ 24 ms with LV mapping.27 In 12 patents with LBBBHF and prolonged QRS duration (185 ⫾ 20 ms), LVAT was reported to be 146 ⫾ 18 ms during endocardial mapping with an LVAT/QRS ratio of 62 ⫾ 17%.23 In the present study in a similar but larger group (LBBBHF with QRS duration ⬎151 ms: QRS duration 184 ⫾ 19 ms, n ⫽ 28), LVAT was 160 ⫾ 22 ms and LVAT/QRS duration was 87 ⫾ 8%, i.e., exceeding previously reported values. Thus, although intra-LV wave-front vectors may differ,23,24 epicardial recording from the inferolateral basal left ventricle accurately reports terminal LV activation, and the LVAT measurement permitted comparison of terminal LV activation delays among and within different groups. In patients with HF with narrow QRS configuration (⬍120 ms), QRS duration was nevertheless wider compared with the control group, in agreement with previous observations.28 To my knowledge, there are no data for LV mapping in this group. The present study demonstrated that LVAT was significantly longer than in the control group, although there was no correlation between LVAT and QRS duration, in contrast to other tested groups. LVAT was ⬍100 ms in 77% of patients, i.e., a low probability of encountering delay. In these, the effect of cardiac resynchronization therapy, i.e., LV pre-excitation of an already relatively early activated region, is uncertain. Because “narrow” QRS duration has been defined variously as ⬍120 or ⬍130 ms (or ⬍150 ms) in different cardiac resynchronization therapy trials and 1 study demonstrated a positive cardiac resynchronization therapeutic effect for QRS dura-
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tion 120 to 130 ms but not for ⬍120 ms, these groups were compared.2,6 When QRS duration was 120 to 130 ms, LVAT was longer compared with the NQRSHF group (98 ⫾ 19 vs 82 ⫾ 22 ms, p ⫽ 0.052) and the probability of encountering a significant LV delay ⬎100 ms almost doubled from 23% to 44%. In the presence of LBBB in patients with HF, inferolateral basal activation delay exceeded 100 ms in 47 of 54 patients (87%). LVAT correlated strongly with QRS duration (Figure 4), suggesting that in this group LVAT may be estimated accurately from surface QRS duration. Previous studies have reported absolute inferolateral delays of approximately 90 ms by LV lead activation times10 and 109 ⫾ 19 and 113 ⫾ 12 ms by electroanatomical mapping of the LV endocardial surface23,27 with an LVAT/QRS duration ratio (indicating the relation of recorded LV activation to terminal LV depolarization) of 60% to 75%.10,23 In contrast, in this study in a larger group of similar patients with LBBBHF, LVAT was 136 ⫾ 33 ms and LVAT/QRS duration was 84 ⫾ 11% (Figure 3), i.e., exceeding previously reported values, illustrating the advantage of epicardial inferolateral basal LV recording to report terminal LV activation. The present study revealed a wide LVAT range in LBBBHF (Figures 2 and 3). Previous LV mapping also reported variation in LV activation in patients with LBBBHF. Minimal LV activation delay in some patients contrasted with longer times in others, possibly related to the longer trans-septal conduction and development of lines of conduction block.24,25 The present results demonstrated that 13% of patients with LBBBHF had an inferolateral LV conduction delay of 80 ⫾ 14 ms, similar to patients with HF and narrow QRS duration. Possibly this group may be less responsive to cardiac resynchronization therapy with LV leads deployed to the inferolateral left ventricle, despite the presence of LBBB. In this study, the probability of encountering LV conduction delays ⬎100 ms varied with QRS duration. When QRS duration was 120 to 130 ms, the probability was ⬍50%, but when QRS duration exceeded 150 ms, this probability increased to 100% and maximum LVAT values were observed in this group. This may contribute to more consistent cardiac resynchronization therapeutic response rates reported with wider QRS duration configurations in patients with LBBB.6,29,30 The current cardiac resynchronization therapy selection criterion of wide QRS duration in HF patients includes RBBB, although these represent ⱕ10% of patients with HF enrolled in trials.4,6 The mechanism underlying any benefit is unclear, because pacing-induced LV pre-excitation should not be beneficial in RBBB, unless there are concealed coexisting LV conduction delays that may expose these patients to adverse effects similarly to LBBB. However, data for LV mapping in patients with RBBBHF are scant. One previous report of 6 patients demonstrated the presence of LV delays equivalent to those found in LBBB. The investigators suggested that this formed the substrate necessary for cardiac resynchronization therapeutic response.27 However, response to cardiac resynchronization therapy of patients with RBBB and LV dysfunction has been inconsistent.7–9 The present results, drawn from a larger group of patients, extend understanding of LV acti-
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Figure 6. Characteristics of patients with RBBBHF and LV activation delays. (A) Two electrographic tracings illustrate wide variations in LV activation. LVAT was 65 ms (top) versus 140 ms (bottom). (B) LV ejection fraction (LVEF) (top) and QRS duration (QRSd) (bottom) in patients with RBBBHF and LVATs similar to those with LBBBHF (LVAT ⫽ LBBBHF, n ⫽ 7) (black bar) compared with those who did not differ from those with NQRSHF, i.e., without LV delay (LVAT ⫽ NQRSHF, n ⫽ 17) (white bar). Those with LV conduction delay were characterized by poorer LV function (LV ejection fraction 18 ⫾ 5 vs 26 ⫾ 9%, *p ⬍0.03) and wider QRS durations (175 ⫾ 16 vs 158 ⫾ 18 ms, #p ⬍0.05). Abbreviations as in Figure 1.
vation in RBBBHF. When QRS duration was ⬎150 ms, i.e., a group considered to have greater cardiac resynchronization therapeutic response rates, LV conduction delay exceeded 100 ms in only 52% of cases compared with 100% when this degree of QRS prolongation was caused by LBBB. Although severe LVAT delays indistinguishable from LBBBHF and identical to those reported by Fantoni et al27 were also observed in the present study, these occurred in only 23% of patients with RBBBHF. In agreement with Fantoni et al,27 these patients were characterized by poor LV function (LV ejection fraction ⬍20%). However, when all patients with RBBBHF were considered together, extent of LV activation delay (100 ⫾ 24 ms) was less than in LBBBHF and demonstrated wide variation (60 to 155 ms, median 100; Figures 2, 3, and 6). Patients with nonischemic disease had significantly prolonged LV conduction delays. In most patients (17 of 31, 55%), LVAT did not differ from patients with NQRSHF, indicating preservation of LV activation. The benefit of cardiac resynchronization therapy in these patients is uncertain because LV pre-excitation of an already early activated region would be expected to be redundant. Thus, inconsistent responses to cardiac resynchronization therapy may be anticipated when this treatment is applied generally to patients with RBBBHF with unmapped, and likely varying, LV conduction delays.
1. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352: 1539 –1549. 2. Beshai JF, Grimm RA, Nagueh SF, Baker JH II, Beau SL, Greenberg SM, Pires LA, Tchou PJ. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 2007;357:2461– 2471. 3. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan J III, St John Sutton M, De Sutter J, Murillo J. Results of the predictors of response to CRT (PROSPECT) trial. Circulation 2008;117:2608 – 2616. 4. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346: 1845–1853. 5. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873– 880. 6. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM. Cardiac resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350:2140 –2150. 7. Egoavil CA, Ho RT, Greenspon AJ, Pavri BB. Cardiac resynchronization therapy in patients with right bundle branch block: analysis of
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17.
18.
pooled data from the MIRACLE and Contak CD trials. Heart Rhythm 2005;2:611– 615. Byrne MJ, Helm RH, Daya S, Osman NF, Halperin HR, Berger RD, Kass DA, Lardo AC. Diminished left ventricular dyssynchrony and impact of resynchronization in failing hearts with right versus left bundle branch block. J Am Coll Cardiol 2007;50:1484 –1490. Garrigue S, Reuter S, Labeque JN, Jais P, Hocini M, Shah DC, Haissaguerre M, Clementy J. Usefulness of biventricular pacing in patients with congestive heart failure and right bundle branch block. Am J Cardiol 2001;88:1436 –1441, A1438. Singh JP, Fan D, Heist EK, Alabiad CR, Taub C, Reddy V, Mansour M, Picard MH, Ruskin JN, Mela T. Left ventricular lead electrical delay predicts response to cardiac resynchronization therapy. Heart Rhythm 2006;3:1285–1292. Botto GL, Mantica M, La Rosa C, D’Onofrio A, Molon G, Villani GQ, Scaccia A, Ciardiello C. Inter-ventricular delay measured at implant can enhance prediction of responder to CRT in heart failure patients. Heart Rhythm 2008;5(suppl):S137. Varma N. Left ventricular conduction delays in response to right ventricular apical pacing. Influence of LV dysfunction and bundle branch block. J Cardiovasc Electrophsyiol 2008;19:114 –122. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539 –542. Leclerq CKD. Retiming the failing heart: principles and current clinical status of cardiac resynchronization. J Am Coll Cardiol 1999;39: 194 –201. Baldasseroni S, Opasich C, Gorini M, Lucci D, Marchionni N, Marini M, Campana C, Perini G, Deorsola A, Masotti G, Tavazzi L, Maggioni AP. Left bundle branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am Heart J 2002;143:398 – 405. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, Kutalek SP, Sharma A. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial. JAMA 2002;288: 3115–3123. Spragg DD, Akar FG, Helm RH, Tunin RS, Tomaselli GF, Kass DA. Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts. Cardiovasc Res 2005;67: 77– 86. Castellant P, Fatemi M, Bertault-Valls V, Etienne Y, Blanc JJ. Cardiac resynchronization therapy: “nonresponders” and “hyperresponders”. Heart Rhythm 2008;5:193–197.
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19. Shukla HH, Hellkamp AS, James EA, Flaker GC, Lee KL, Sweeney MO, Lamas GA. Heart failure hospitalization is more common in pacemaker patients with sinus node dysfunction and a prolonged paced QRS duration. Heart Rhythm 2005;2:245–251. 20. Butter C, Auricchio A, Stellbrink C, Fleck E, Ding J, Yu Y, Huvelle E, Spinelli J. Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients. Circulation 2001;104: 3026 –3029. 21. Suga H, Goto Y, Yaku H, Futaki S, Ohgoshi Y, Kawaguchi O. Simulation of mechanoenergetics of asynchronously contracting ventricle. Am J Physiol 1990;259:R1075–R1082. 22. Vassallo JA, Cassidy DM, Marchlinski FE, Buxton AE, Waxman HL, Doherty JU, Josephson ME. Endocardial activation of left bundle branch block. Circulation 1984;69:914 –923. 23. Rodriguez LM, Timmermans C, Nabar A, Beatty G, Wellens HJ. Variable patterns of septal activation in patients with left bundle branch block and heart failure. J Cardiovasc Electrophysiol 2003;14: 135–141. 24. Auricchio A, Fantoni C, Regoli F, Carbucicchio C, Goette A, Geller C, Kloss M, Klein H. Characterization of left ventricular activation in patients with heart failure and left bundle branch block. Circulation 2004;109:1133–1139. 25. Jia P, Ramanathan C, Ghanem RN, Ryu K, Varma N, Rudy Y. Electrocardiographic imaging of cardiac resynchronization therapy in heart failure: observation of variable electrophysiologic responses. Heart Rhythm 2006;3:296 –310. 26. Durrer D, van Dam RT, Freud GE, Janse MJ, Meijler FL, Arzbaecher RC. Total excitation of the isolated human heart. Circulation 1970; 41:899 –912. 27. Fantoni C, Kawabata M, Massaro R, Regoli F, Raffa S, Arora V, Salerno-Uriarte JA, Klein HU, Auricchio A. Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: a detailed analysis using three-dimensional non-fluoroscopic electroanatomic mapping system. J Cardiovasc Electrophysiol 2005;16:112–120. 28. 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 – 482. 29. Nelson GS, Curry CW, Wyman BT, Kramer A, Declerck J, Talbot M, Douglas MR, Berger RD, McVeigh ER, Kass DA. Predictors of systolic augmentation from left ventricular preexcitation in patients with dilated cardiomyopathy and intraventricular conduction delay. Circulation 2000;101:2703–2709. 30. Auricchio A, Stellbrink C, Butter C, Sack S, Vogt J, Misier AR, Bocker D, Block M, Kirkels JH, Kramer A, Huvelle E. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol 2003;42:2109 –2116.
delays. The ability to derive LV conduction delays from the surface electrocardiogram is therefore a critical element to the evaluation of the role of QRS duration as a selection criterion and its acknowledged limitations. In this study, I hypothesized that terminal inferolateral LV activation during intrinsic conduction in patients with HF would vary in absolute terms and differ in relation to QRS width and configuration. Methods The method has been previously described.12 Briefly, the study population consisted of consecutive patients undergoing routine electrophysiologic study and/or cardiac resynchronization therapy. The control group (n ⫽ 30) had normal LV function and normal QRS configuration. Patients with LV dysfunction (HF, LV ejection fraction ⬍40%) were categorized into groups according to baseline conduction pattern: those with normal QRS duration (⬍120 ms) and configuration (NQRSHF, n ⫽ 35), those with RBBB (RBBBHF, n ⫽ 31), and those with left bundle branch block (LBBBHF, n ⫽ 54). When QRS duration was ⱖ120 ms, LBBB was diagnosed by an RsR= complex in leads V6 and rS or QS deflection in lead V1 or V2 and RBBB by a dominant terminal R wave in lead V1 (triphasic complex rSR, qR, or R). Patients were excluded if they had atrioventricular block and no intrinsic conduction, or when an LV electrogram was not clearly inscribed during coronary sinus mapping. All www.AJConline.org
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Figure 1. (Left) Schematic of terminal LV depolarization (LVAT) in the epicardium of the inferolateral base of the left ventricle (LV) (shaded) recorded by electrode mapping along the atrioventricular ring through the coronary sinus (CS). (Right) Representative tracing from a control patient with a structurally normal heart and normal QRS configuration and duration. Bipolar electrograms displayed are recorded from electrode catheters sited at the proximal and distal coronary sinus (CS px, CS ds), His bundle (His), and right ventricular apex (RVA). Table 1 Patient demographics
Control NQRSHF RBBBHF LBBBHF
Patients
Age (yrs)
Men
Patients With AF
Patients With AA Rx
Patients With CAD/NICM
LVEF (%)
30 35 31 54
61 ⫾ 19 64 ⫾ 11 70 ⫾ 13 66 ⫾ 16
18 (60%) 28 (80%) 24 (77%) 45 (83%)
0 (0%) 5 (14%) 6 (19%) 11 (20%)
0 (0%) 4 (11%) 6 (19%) 8 (15%)
0/0 20 (57%)/15(43%) 23 (74%)/8 (26%) 30 (56%)/24 (44%)
Normal 25 ⫾ 8 24 ⫾ 8 22 ⫾ 8*
* p ⫽ 0.043 versus NQRSHF. AA Rx ⫽ antiarrhythmic drug therapy with amiodarone; AF ⫽ atrial fibrillation; CAD ⫽ coronary artery disease; LVEF ⫽ LV ejection fraction; NICM ⫽ nonischemic cardiomyopathy. Table 2 QRS duration and inferolateral left ventricular activation time during intrinsic conduction Group Control NQRSHF RBBBHF LBBBHF
QRSd (ms)
LVAT (ms)
QRSd ⫺ LVAT (ms)
82 ⫾ 13 (65–110) 104 ⫾ 10* (80–120) 165 ⫾ 18* (132–206) 161 ⫾ 29* (121–233)
55 ⫾ 18 (30–95) 82 ⫾ 22* (40–135) 100 ⫾ 24* (60–155) 136 ⫾ 33* (67–200)
27 ⫾ 16 22 ⫾ 21 65 ⫾ 23* 25 ⫾ 16
Values are means ⫾ SDs (ranges). * p ⬍0.001 versus control. QRSd ⫽ QRS duration; LVAT ⫽ left ventricular activation time.
patients provided informed written consent, conforming to institutional guidelines. Electrograms were recorded from a multipolar electrode catheter (at electrophysiologic study or from the coronary sinus sheath for LV lead implantation) positioned in the coronary sinus so the distal electrode marked the inferolateral position (according to the 17-segment nomenclature13) on the mitral ring (Figure 1). Catheter position was verified with fluoroscopy in left and right oblique views. Surface electrocardiographic leads and intracardiac signals (bipolar, filtered 30 to 500 Hz) were simultaneously recorded and stored digitally on optical disk (Prucka Engineering, Houston, Texas). Measurements
were made with electronic callipers at screen speeds of 200 to 400 mm/s. All activation times were referenced to earliest onset of the QRS complex in any lead. QRS duration was measured manually from the beginning of the earliest QRS complex in any lead to the end in any lead using simultaneously displayed electrocardiographic signals. Inferolateral LV activation time (LVAT, milliseconds) was assessed during coronary sinus electrode mapping, measured as the interval between QRS onset (earliest in any surface lead) and the intrinsicoid of the inscribed LV electrogram (i.e., the point at which the largest rapid deflection crossed the baseline). An LVAT value ⬎100 ms was considered significant. The relation of inferolateral LV activation to terminal ventricular depolarization was indexed by the difference between the end of the QRS complex and LVAT (QRS duration minus LVAT). Data are reported as mean ⫾ SD. Comparisons between groups were done by unpaired t test (SPSS 13, SPSS, Inc., Chicago, Illinois). A p value ⬍0.05 was considered statistically significant. Simple linear regression was used to study the association between LVAT and QRS duration. Results Demographics of study groups are presented in Table 1 and their data in Table 2. In HF (n ⫽ 120, LV ejection fraction 23 ⫾ 8%), groups (NQRSHF, LBBBHF, and
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Figure 2. (Top) Representative surface electrocardiographic recordings and intracardiac electrograms during intrinsic conduction illustrating mean LVAT values in each HF group. LVAT in the LBBBHF group exceeded that in the RBBBHF group in these examples, which were greater than those in the NQRSHF group. (Bottom) LVAT exceeded 100 ms infrequently (23%) in the NQRSHF group but in most patients (87%) with LBBBHF. Abbreviations as in Figure 1.
RBBBHF) were matched for age, pathology, incidence of atrial fibrillation, and use of amiodarone. Figure 2 shows representative electrograms and LVAT frequency distributions and Figure 3 displays comparisons between groups. Intrinsic conduction in the control group resulted in a QRS duration of 82 ⫾ 13 ms. Inferolateral LV activation (LVAT) occurred 55 ⫾ 18 ms after QRS onset, 27 ⫾ 16 ms before the end of the QRS complex. Increasing QRS duration in different patients correlated with more prolonged LVAT (r ⫽ 0.52, p ⫽ 0.004; Figure 4). LVAT did not exceed 100 ms in any patient. In the NQRSHF group, QRS duration and LVAT were 22 ⫾ 3 and 27 ⫾ 5 ms longer, respectively, compared with the control group, despite QRS configuration being normal in the 2 groups (QRS duration 104 ⫾ 10 vs 82 ⫾ 13 ms, p ⬍0.001; LVAT 82 ⫾ 22 vs 55 ⫾ 18 ms, p ⬍0.001). LVAT occurred 22 ⫾ 21 ms before QRS termination, which was not different from the control group (p ⫽ NS). However, LVAT did not correlate with QRS duration in the NQRSHF group (r ⫽ 0.25, p ⫽ 0.15; Figure 4). QRS duration and LVAT did not differ in patients with ischemic and nonischemic cardiomyopathy (QRS duration 106 ⫾ 10 vs
101 ⫾ 10 ms, LVAT 79 ⫾ 21 vs 86 ⫾ 22 ms, respectively, p ⫽ NS). LVAT exceeded 100 ms in 8 of 35 patients (23%). In the LBBBHF group, QRS duration (161 ⫾ 29 ms) and LVAT (136 ⫾ 33 ms) during intrinsic conduction were prolonged compared with the control and NQRSHF groups (p ⬍0.001). LVAT occurred 25 ⫾ 16 ms before QRS termination, which was not different from the control or NQRSHF group (p ⫽ NS), indicating that the inferolateral LV region participated similarly in terminal ventricular depolarization in these groups. Increasing QRS duration in the LBBBHF group correlated strongly with more prolonged LVAT (r ⫽ 0.88, p ⬍0.001; Figure 4). LVAT/QRS ratio was 84 ⫾ 11%. LVAT exceeded 100 ms in 47 of 54 patients (87%). LVAT in the remaining 7 patients (QRS duration 130 ⫾ 8 ms) was 80 ⫾ 14 ms, similar to the NQRSHF group (p ⫽ NS). QRS duration and LVAT did not differ in patients with ischemic and nonischemic cardiomyopathy (QRS duration 161 ⫾ 30 vs 161 ⫾ 27 ms, LVAT 126 ⫾ 35 vs 138 ⫾ 30 ms, respectively, p ⫽ NS). The LBBBHF group was subdivided into 3 groups according to QRS duration ranges of 120 to 130, 131 to 150, and ⬎151 ms (Figure 5). When QRS duration was 120 to
Heart Failure/LV Conduction Delays in Heart Failure
*
200
*
LVAT (ms)
150
*
100
50
0 CONTROL
NQRSHF
RBBBHF
LBBBHF
Figure 3. LVAT data are presented in Tukey box plots to illustrate degree of data dispersion, which was minimal in the control group and maximal in the LBBBHF group. Delays were greater in all HF groups versus the control group (p ⬍0.001). Delays in the LBBBHF group exceeded those in the RBBBHF group and delays in these 2 groups were greater than that in the NQRSHF group. Compared with an LVAT equal to 100 ms (dashed line), LVATs in all control patients were shorter. In the NQRSHF group, the interquartile range (box length) was ⬍100 ms contrasting with the LBBBHF group, where the range was ⬎100 ms. In the RBBBHF group, the box crossed this value and the median (cross bar on box) equalled 100 ms (*p ⬍0.001 vs control and between groups).
130 ms (9 of 54 patients, 17%), QRS duration was 126 ⫾ 4 ms and LVAT was 98 ⫾ 19 ms (range 67 to 125). LVAT exceeded 100 ms in 4 of 9 patients (44%). LVAT was 16 ⫾ 7 ms longer compared with the NQRSHF group (98 ⫾ 19 vs 82 ⫾ 22 ms, p ⫽ 0.052). When QRS duration was 131 to 150 ms (17 of 54 patients, 31%), QRS duration was 141 ⫾ 6 ms and LVAT was 117 ⫾ 21 ms (range 60 to 150). LVAT exceeded 100 ms in 15 of 17 patients (88%). In patients with LBBBHF in whom QRS duration exceeded 151 ms (28 of 54 patients, 52%), QRS duration was 184 ⫾ 19 ms and LVAT was 160 ⫾ 22 ms (range 106 to 200). LVAT/QRS duration ratio was 87 ⫾ 8%. LVAT exceeded 100 ms in 28 of 28 patients (100%). In the RBBBHF group, QRS duration during intrinsic conduction was wider compared with the control and NQRSHF groups (p ⬍0.001). LVAT was 100 ⫾ 24 ms, i.e., prolonged compared with the control or NQRSHF group (p ⬍0.001), indicating the presence of significant LV conduction delay. Compared with the LBBBHF group, however, QRS duration did not differ (RBBBHF 165 ⫾ 18 ms vs LBBBHF 161 ⫾ 29 ms, p ⫽ NS) and LV conduction delay was less (RBBBHF 100 ⫾ 24 ms vs LBBBHF 136 ⫾ 33 ms, p ⬍0.001). QRS duration ⬎150 ms was recorded in 27 of 31 patients with RBBBHF and LVAT exceeded 100 ms in 14 of 27 (52%). QRS width correlated with inferolateral LV activation delay but not as strongly compared with the LBBBHF group (r ⫽ 0.44, p ⫽ 0.02; Figure 4). Inferolateral LV depolarization in the RBBBHF group occurred 65 ⫾ 23 ms before QRS termination, i.e., LV activation, although
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delayed in absolute terms, was completed earlier relative to overall ventricular depolarization compared with other groups (p ⬍0.001). LV activation delay varied widely in the RBBBHF group (median 100 ms, range 60 to 155; Figures 2 and 3). Although QRS duration did not differ, LVAT in patients with nonischemic cardiomyopathy was significantly longer than in those with ischemic disease (QRS duration 166 ⫾ 14 vs 164 ⫾ 19 ms, p ⫽ NS; LVAT 125 ⫾ 19 vs 97 ⫾ 28 ms, respectively, p ⫽ 0.016). Overall, LVAT was ⬍100 ms in 17 of 31 patients (55%, 82 ⫾ 12 ms) and these did not differ from the NQRSHF group (p ⫽ NS), indicating that inferolateral LV depolarization was not delayed. However, in 14 of 31 patients (45%) with RBBBHF, LVAT was ⱖ100 ms (mean 121 ⫾ 18). This group was characterized by wider QRS duration (172 ⫾ 14 vs 158 ⫾ 18 ms, p ⬍0.03) and lower LV ejection fraction (21 ⫾ 6% vs 26 ⫾ 9%, p ⬍0.02). In 7 patients (23% of RBBBHF group), LVAT exceeded 120 ms and did not differ from the LBBBHF group (135 ⫾ 13 vs 136 ⫾ 33 ms, p ⫽ NS). These patients (compared with those with RBBBHF without concomitant LV conduction delay) had poorer LV function (LV ejection fraction 18 ⫾ 5%, p ⬍0.03) and more prolonged QRS durations (175 ⫾ 16 ms, p ⬍0.05; Figure 6). Discussion This study is the first to quantify in a large population the relation among QRS width, QRS morphology, and LVAT. Incidence of significant LV activation delays (⬎100 ms) varied in patients with HF separated according to QRS configuration, occurring most frequently with LBBB, at an intermediate rate (45%) in RBBB, and in only 23% when QRS was normal. No control patient demonstrated LV conduction delays ⬎100 ms. QRS duration correlated strongly with late inferolateral LV activation in LBBBHF. When QRS duration was ⬎150 ms, LVAT exceeded 100 ms in 100% of patients with LBBBHF but in only 52% of patients with RBBBHF. Cardiac resynchronization therapy is based on the premise that paced pre-excitation of late depolarized and contracting LV regions in patients with LBBB reverses deleterious mechanical effects.14 Current echocardiographic measurements have not been effective discriminators of potential responders.2,3 In contrast, the prognostic import of LV conduction delays is indicated by the observations that a wide QRS configuration generated by LBBB or right ventricular apical pacing, which delay inferolateral LV electrical activation, increase mortality, whereas LV paced preexcitation of this same region with cardiac resynchronization therapy improves survival.1,15,16 Implicitly, pacing a LV region that is not subject to delayed activation may not confer benefit. Conduction delay triggers regional molecular and metabolic remodeling.17 LBBB occurring in structurally normal hearts delayed inferolateral LV depolarization to 116 ⫾ 10 ms (range 87 to 135, median 115).12 Possibly a longer delay may promote greater adverse remodeling and may explain induction of cardiomyopathy in only some patients by this conduction lesion, readily reversible with cardiac resynchronization therapy.18 During right ventricular apical pacing, longer QRS duration, which in
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Figure 4. Correlations between LVATs and QRS width show the strongest correlation for LBBBHF. There was no significant correlation for NQRSHF.
this condition is tightly linked to inferolateral LV conduction delay,12 was associated with greater deleterious effect.19 The clinical value of this delay becomes evident during cardiac resynchronization therapy. Greater delay in patients with LBBB correlated with better cardiac resynchronization therapeutic response.10 LV leads placed inferolaterally, the site of terminal LV activation, improved response.20 A delay recorded at the LV lead location exceeding 90 to 115 ms appeared to be significant in models21 and correlated with cardiac resynchronization therapeutic effect in clinical studies,10,11,20 and, hence, a cutpoint of 100 ms was used in this study. In support of this threshold, this value was observed to exceed 2 SDs from the mean in the control group. Terminal LV depolarization may not be reported by estimation of LV activation delay to LV electrode sites due to positional variability. For example, anteriorly placed leads report earlier activation in absolute timings and relative to QRS forces.10,20 This limitation was avoided in the present study by consistently assessing a single LV region
involved in terminal activation. The method used a fundamental LV characteristic, i.e., depolarization proceeds from the endocardium to the epicardium and from the apex to the base. Terminal LV depolarization occurs in the inferolateral base adjacent to the atrioventricular sulcus. Several studies using different techniques including intraoperative epicardial mapping, endocardial catheter or electroanatomical mapping,22–24 epicardial imaging,25 or isolated heart studies have demonstrated that the inferolateral area is depolarized last during intrinsic conduction in normal subjects and during LBBB26 and only exceptionally anterolaterally. This pattern of LV activation was retained during RBBB.27 The epicardium of the inferolateral base of the left ventricle may be conveniently mapped by LV electrograms recorded through the coronary sinus. The present results demonstrated that depolarization (LVAT) occurred approximately 25 ms before final QRS inscription in the control, NQRSHF, and LBBBHF groups (because right ventricular delays determine final QRS forces in RBBBHF, terminal LV activation occurred earlier during the QRS complex despite ab-
Heart Failure/LV Conduction Delays in Heart Failure
200
*
p < 0.03 p = 0.052
LVAT (ms)
150
100
50
0
NQRSHF
120-130 ms LBBBHF
131-150 ms LBBBHF
151+ ms LBBBHF
Figure 5. Comparison of LVATs in the NQRSHF and LBBBHF groups divided into 3 subgroups according to QRS durations of 120 to 130, 131 to 150, and ⬎151 ms. Data are presented in Tukey box plots to illustrate degree of data dispersion. The interquartile range (box length) was ⬎100 ms (dashed line) only when QRS duration exceeded 130 ms (*p ⬍0.001 vs other groups).
solute LV activation being delayed). In further support of this measurement reflecting terminal LV depolarization, absolute LVAT values in this study reported similar or later terminal LVATs compared with previously reported endocardial mapping. For example, an LVAT of 55 ⫾ 18 ms in the control group was similar to 58 ⫾ 6 ms reported by Rodriguez et al.23 In patients with RBBBHF with poorer LV function, LVAT was 135 ⫾ 13 ms compared with 135 ⫾ 24 ms with LV mapping.27 In 12 patents with LBBBHF and prolonged QRS duration (185 ⫾ 20 ms), LVAT was reported to be 146 ⫾ 18 ms during endocardial mapping with an LVAT/QRS ratio of 62 ⫾ 17%.23 In the present study in a similar but larger group (LBBBHF with QRS duration ⬎151 ms: QRS duration 184 ⫾ 19 ms, n ⫽ 28), LVAT was 160 ⫾ 22 ms and LVAT/QRS duration was 87 ⫾ 8%, i.e., exceeding previously reported values. Thus, although intra-LV wave-front vectors may differ,23,24 epicardial recording from the inferolateral basal left ventricle accurately reports terminal LV activation, and the LVAT measurement permitted comparison of terminal LV activation delays among and within different groups. In patients with HF with narrow QRS configuration (⬍120 ms), QRS duration was nevertheless wider compared with the control group, in agreement with previous observations.28 To my knowledge, there are no data for LV mapping in this group. The present study demonstrated that LVAT was significantly longer than in the control group, although there was no correlation between LVAT and QRS duration, in contrast to other tested groups. LVAT was ⬍100 ms in 77% of patients, i.e., a low probability of encountering delay. In these, the effect of cardiac resynchronization therapy, i.e., LV pre-excitation of an already relatively early activated region, is uncertain. Because “narrow” QRS duration has been defined variously as ⬍120 or ⬍130 ms (or ⬍150 ms) in different cardiac resynchronization therapy trials and 1 study demonstrated a positive cardiac resynchronization therapeutic effect for QRS dura-
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tion 120 to 130 ms but not for ⬍120 ms, these groups were compared.2,6 When QRS duration was 120 to 130 ms, LVAT was longer compared with the NQRSHF group (98 ⫾ 19 vs 82 ⫾ 22 ms, p ⫽ 0.052) and the probability of encountering a significant LV delay ⬎100 ms almost doubled from 23% to 44%. In the presence of LBBB in patients with HF, inferolateral basal activation delay exceeded 100 ms in 47 of 54 patients (87%). LVAT correlated strongly with QRS duration (Figure 4), suggesting that in this group LVAT may be estimated accurately from surface QRS duration. Previous studies have reported absolute inferolateral delays of approximately 90 ms by LV lead activation times10 and 109 ⫾ 19 and 113 ⫾ 12 ms by electroanatomical mapping of the LV endocardial surface23,27 with an LVAT/QRS duration ratio (indicating the relation of recorded LV activation to terminal LV depolarization) of 60% to 75%.10,23 In contrast, in this study in a larger group of similar patients with LBBBHF, LVAT was 136 ⫾ 33 ms and LVAT/QRS duration was 84 ⫾ 11% (Figure 3), i.e., exceeding previously reported values, illustrating the advantage of epicardial inferolateral basal LV recording to report terminal LV activation. The present study revealed a wide LVAT range in LBBBHF (Figures 2 and 3). Previous LV mapping also reported variation in LV activation in patients with LBBBHF. Minimal LV activation delay in some patients contrasted with longer times in others, possibly related to the longer trans-septal conduction and development of lines of conduction block.24,25 The present results demonstrated that 13% of patients with LBBBHF had an inferolateral LV conduction delay of 80 ⫾ 14 ms, similar to patients with HF and narrow QRS duration. Possibly this group may be less responsive to cardiac resynchronization therapy with LV leads deployed to the inferolateral left ventricle, despite the presence of LBBB. In this study, the probability of encountering LV conduction delays ⬎100 ms varied with QRS duration. When QRS duration was 120 to 130 ms, the probability was ⬍50%, but when QRS duration exceeded 150 ms, this probability increased to 100% and maximum LVAT values were observed in this group. This may contribute to more consistent cardiac resynchronization therapeutic response rates reported with wider QRS duration configurations in patients with LBBB.6,29,30 The current cardiac resynchronization therapy selection criterion of wide QRS duration in HF patients includes RBBB, although these represent ⱕ10% of patients with HF enrolled in trials.4,6 The mechanism underlying any benefit is unclear, because pacing-induced LV pre-excitation should not be beneficial in RBBB, unless there are concealed coexisting LV conduction delays that may expose these patients to adverse effects similarly to LBBB. However, data for LV mapping in patients with RBBBHF are scant. One previous report of 6 patients demonstrated the presence of LV delays equivalent to those found in LBBB. The investigators suggested that this formed the substrate necessary for cardiac resynchronization therapeutic response.27 However, response to cardiac resynchronization therapy of patients with RBBB and LV dysfunction has been inconsistent.7–9 The present results, drawn from a larger group of patients, extend understanding of LV acti-
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Figure 6. Characteristics of patients with RBBBHF and LV activation delays. (A) Two electrographic tracings illustrate wide variations in LV activation. LVAT was 65 ms (top) versus 140 ms (bottom). (B) LV ejection fraction (LVEF) (top) and QRS duration (QRSd) (bottom) in patients with RBBBHF and LVATs similar to those with LBBBHF (LVAT ⫽ LBBBHF, n ⫽ 7) (black bar) compared with those who did not differ from those with NQRSHF, i.e., without LV delay (LVAT ⫽ NQRSHF, n ⫽ 17) (white bar). Those with LV conduction delay were characterized by poorer LV function (LV ejection fraction 18 ⫾ 5 vs 26 ⫾ 9%, *p ⬍0.03) and wider QRS durations (175 ⫾ 16 vs 158 ⫾ 18 ms, #p ⬍0.05). Abbreviations as in Figure 1.
vation in RBBBHF. When QRS duration was ⬎150 ms, i.e., a group considered to have greater cardiac resynchronization therapeutic response rates, LV conduction delay exceeded 100 ms in only 52% of cases compared with 100% when this degree of QRS prolongation was caused by LBBB. Although severe LVAT delays indistinguishable from LBBBHF and identical to those reported by Fantoni et al27 were also observed in the present study, these occurred in only 23% of patients with RBBBHF. In agreement with Fantoni et al,27 these patients were characterized by poor LV function (LV ejection fraction ⬍20%). However, when all patients with RBBBHF were considered together, extent of LV activation delay (100 ⫾ 24 ms) was less than in LBBBHF and demonstrated wide variation (60 to 155 ms, median 100; Figures 2, 3, and 6). Patients with nonischemic disease had significantly prolonged LV conduction delays. In most patients (17 of 31, 55%), LVAT did not differ from patients with NQRSHF, indicating preservation of LV activation. The benefit of cardiac resynchronization therapy in these patients is uncertain because LV pre-excitation of an already early activated region would be expected to be redundant. Thus, inconsistent responses to cardiac resynchronization therapy may be anticipated when this treatment is applied generally to patients with RBBBHF with unmapped, and likely varying, LV conduction delays.
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