Patients with non-left bundle branch block (LBBB) morphologies are thought to derive less benefit from cardiac resynchronization therapy (CRT) than those with LBBB. However, some patients do exhibit improvement. The characteristics associated with a response to CRT in patients with non-LBBB morphologies are unknown. Clinical, electrocardiographic, and echocardiographic data were collected from 850 consecutive patients presenting for a new CRT device. For inclusion, all patients had a left ventricular ejection fraction of ≤35%, a QRS duration of ≥120 ms, and baseline and follow-up echocardiograms available. Patients with a paced rhythm or LBBB were excluded. The response was defined as an absolute decrease in left ventricular end-systolic volume of ≥10% from baseline. Multivariate models were constructed to identify variables significantly associated with the response and long-term outcomes. A total of 99 patients met the inclusion criteria. Of these 99 patients, 22 had right bundle branch block and 77 had nonspecific intraventricular conduction delay; 52.5% met the criteria for response. On multivariate analysis, the QRS duration was the only variable significantly associated with the response (odds ratio per 10-ms increase 1.23, 95% confidence interval 1.01 to 1.52, p = 0.048). During a mean follow-up of 5.4 ± 0.9 years, 65 patients died or underwent heart transplant or left ventricular assist device placement. On multivariate analysis, the QRS duration was inversely associated with poor long-term outcomes (hazard ratio per 10-ms increase 0.79, 95% confidence interval 0.66 to 0.94, p = 0.005). In patients with advanced heart failure and non-LBBB morphologies, a wider baseline QRS duration is an important determinant of enhanced reverse ventricular remodeling and improved long-term outcomes after CRT.
The large majority of patients enrolled in the major clinical trials of cardiac resynchronization therapy (CRT) have had left bundle branch block (LBBB). As such, patients with QRS morphologies other than LBBB (right bundle branch block [RBBB] and nonspecific intraventricular conduction delay [NSIVCD]) were highly underrepresented. The response to CRT in patients with non-LBBB QRS morphologies is controversial. One important confounder in evaluating the responsiveness in this patient population is the baseline QRS duration. It has been well established that patients with a wider baseline QRS duration have an increased probability of response to CRT compared to those with a narrower duration. In addition, most patients with non-LBBB QRS morphology have inherently narrower QRS durations than patients with LBBB or right ventricular pacing. Therefore, it has been difficult to determine whether the apparent inferior outcomes after CRT in non-LBBB morphologies are due to the QRS morphology or duration. The aim of the present retrospective cohort study was to determine the baseline factors associated with the response in patients with advanced heart failure presenting for CRT with non-LBBB QRS morphologies, specifically focusing on the effect of the baseline QRS duration.
Methods
The present retrospective study involved the analysis of a cohort of patients who underwent new implantation of a cardiac resynchronization device at the Cleveland Clinic (Cleveland, Ohio) from December 3, 2003 to July 30, 2007. The study was approved by the institutional review board of the Cleveland Clinic for retrospective medical records review and performed according to institutional guidelines. Clinical data were gathered by chart review. For inclusion in the final cohort, all patients had New York Heart Association class II-IV heart failure, left ventricular ejection fraction of ≤35%, QRS duration of ≥120 ms, RBBB or NSIVCD on their baseline electrocardiogram and available pre- and post-CRT echocardiograms, with the post-CRT echocardiogram performed ≥2 months after device implantation.
The echocardiograms were reanalyzed by board-certified cardiologists who were unaware of the clinical outcome using an image archiving and review system (Syngo Dynamics, Siemens AG, Munich, Germany). The left ventricular endocardial border was manually traced in the apical 4-chamber view to determine the left ventricular end-diastolic volume, left ventricular end-systolic volume, and left ventricular ejection fraction. The response was defined as a reduction in the left ventricular end-systolic volume of ≥10% from baseline. Mitral regurgitation was graded on a 9-point scale using multiple gauges of severity according to the 2003 American Society of Echocardiography Guidelines integrated to produce a score as follows: 0 to 3, mild; 3 to 6, moderate; and 7 to 9, severe.
LBBB was defined as a QRS duration of ≥120 ms with a monophasic QS or rS complex in lead V 1 and a monophasic R wave in lead V 6 . RBBB was defined as a QRS duration of ≥120 ms with a deep terminal S wave in leads V 1 and V 6 and an RSR′, wide R, or qR pattern in lead V 1 . NSIVCD was defined as a QRS duration of ≥120 ms, not meeting the criteria for either RBBB or LBBB.
CRT device implantations were performed transvenously in the vast majority of patients by electrophysiologists targeting a lateral or posterolateral vein for the left ventricular lead position. The CRT devices were commonly programmed with an atrioventricular sensed delay of 100 ms and paced delay of 130 ms, with optimization performed according to the standard protocols of the Cleveland Clinic. The medications and dosages were recorded immediately before implantation of the CRT device, with subsequent titration of the medications made at the discretion of the patients’ outpatient physicians. All-cause mortality was assessed using the United States Social Security Death Index.
Continuous variables are presented as the mean ± SD, and dichotomous variables as absolute numbers with percentages. Comparisons between continuous variables were made using Student’s t test for parametric variables and a Mann-Whitney U test for nonparametric variables. Dichotomous variables were compared using Fisher’s exact test. Age, gender, and variables significant on univariate analysis for p <0.2 were entered into forward stepwise multivariate regression models to determine the factors significantly associated with the response and time to death, left ventricular assist device (LVAD) implantation, or heart transplant. Kaplan-Meier curves were created, and a log-rank test was used to compare the interval to death, LVAD implantation, or heart transplant among the patients stratified by the baseline QRS duration. A 2-sided p value of ≤0.05 was considered statistically significant. All analyses were done using Statistical Package for Social Sciences software, version 17.0 (SPSS, Chicago, Illinois).
Results
A total of 865 patients underwent first implantation of a CRT device at our institution from December 3, 2003 to July 30, 2007. From this cohort, 99 met the inclusion criteria and constituted the final cohort, of whom 52 (52.5%) met the criteria for a response. Of the 99 patients, 77 had NSIVCD and 22 RBBB. The follow-up echocardiogram was done at a mean of 13.0 months (interquartile range 6.3 to 16.1) after CRT initiation. The baseline characteristics of the cohort as a whole and stratified by the response are reported in Tables 1 and 2 . The patients meeting the criteria for response had a significantly greater baseline QRS duration (150.3 ± 20.8 vs 142.0 ± 19.4 ms, p = 0.043) and a greater incidence of New York Heart Association class II heart failure at baseline (19% vs 4%, p = 0.03). On multivariate analysis, only the baseline QRS duration remained significantly associated with the response (odds ratio per 10-ms increase 1.23, 95% confidence interval 1.01 to 1.522, p = 0.048).
| Variable | Total Cohort (n = 99) | Responders (n = 52) | Nonresponders (n = 47) | p Value |
|---|---|---|---|---|
| Age (years) | 64.1 ± 11.3 | 65.2 ± 11.0 | 62.9 ± 11.6 | 0.308 |
| Men | 85 (86%) | 42 (80%) | 43 (92%) | 0.156 |
| Precardiac resynchronization therapy QRS duration (ms) | 146.3 ± 20.5 | 150.3 ± 20.8 | 142.0 ± 19.4 | 0.043 ⁎ |
| Implantable cardiac defibrillator | 97 (98%) | 50 (96%) | 47 (100%) | 0.496 |
| Right bundle branch block | 22 (22%) | 10 (19%) | 12 (26%) | 0.478 |
| Ischemic cardiomyopathy | 61 (62%) | 36 (69%) | 25 (53%) | 0.147 |
| Atrial fibrillation | 45 (46%) | 19 (37%) | 26 (55%) | 0.071 |
| Diabetes mellitus | 38 (38%) | 22 (42%) | 16 (34%) | 0.417 |
| Serum creatinine (mg/dl) | 1.4 ± 0.7 | 1.3 ± 0.5 | 1.5 ± 0.9 | 0.192 |
| Smoker | 69 (70%) | 37 (71%) | 32 (68%) | 0.828 |
| Chronic obstructive pulmonary disease | 16 (16%) | 11 (21%) | 5 (11%) | 0.181 |
| Hypertension | 68 (69%) | 38 (73%) | 30 (64%) | 0.388 |
| Hyperlipidemia | 61 (62%) | 34 (65%) | 27 (57%) | 0.535 |
| Previous cerebrovascular accident or transient ischemic attack | 14 (14%) | 7 (14%) | 7 (15%) | 1.0 |
| Serum hemoglobin (g/dl) | 12.9 ± 2.1 | 13.1 ± 2.2 | 12.6 ± 1.9 | 0.261 |
| β-Adrenergic blocker | 80 (81%) | 41 (79%) | 39 (83%) | 0.621 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker | 87 (88%) | 45 (87%) | 42 (89%) | 0.764 |
| Diuretic | 79 (80%) | 41 (79%) | 38 (81%) | 1.0 |
| Nitrates | 40 (40%) | 22 (42%) | 18 (38%) | 0.838 |
| Hydralazine | 18 (18%) | 12 (23%) | 6 (13%) | 0.204 |
| Antiarrhythmic medication | 26 (26%) | 13 (25%) | 13 (28%) | 0.821 |
| Aldosterone antagonist | 30 (30%) | 17 (33%) | 13 (28%) | 0.276 |
| New York Heart Association class | ||||
| 2 | 12 (12%) | 10 (19%) | 2 (4%) | 0.03 |
| 3 | 82 (83%) | 40 (77%) | 42 (89%) | 0.11 |
| 4 | 5 (5%) | 2 (4%) | 3 (6%) | 0.67 |
| Variable | Total (n = 99) | Responders (n = 52) | Nonresponders (n = 47) | p Value |
|---|---|---|---|---|
| Left Ventricular Ejection Fraction (%) | ||||
| Before cardiac resynchronization therapy | 22 ± 7 | 21 ± 7 | 22 ± 7 | 0.44 |
| After cardiac resynchronization therapy | 25 ± 10 | 29 ± 11 | 22 ± 7 | 0.0004 ⁎ |
| Change | 4 ± 9 | 8 ± 9 | −0.7 ± 7 | <0.0001 ⁎ |
| Left ventricular end-diastolic volume (ml) | ||||
| Before cardiac resynchronization therapy | 211 ± 94 | 214 ± 90 | 207 ± 100 | 0.71 |
| After cardiac resynchronization therapy | 196 ± 99 | 162 ± 69 | 231 ± 114 | 0.001 ⁎ |
| Change | −16 ± 60 | −52 ± 48 | 25 ± 46 | <0.0001 ⁎ |
| Left ventricular end-systolic volume (ml) | ||||
| Before cardiac resynchronization therapy | 153 ± 80 | 158 ± 76 | 148 ± 84 | 0.52 |
| After cardiac resynchronization therapy | 141 ± 87 | 109 ± 59 | 177 ± 100 | <0.0001 ⁎ |
| Change | −12 ± 54 | −50 ± 35 | 29 ± 39 | <0.0001 ⁎ |
| Mitral regurgitation (ms) | ||||
| Before cardiac resynchronization therapy | 3 ± 2 | 3 ± 2 | 3 ± 2 | 0.65 |
| After cardiac resynchronization therapy | 3 ± 2 | 3 ± 2 | 4 ± 2 | 0.02 ⁎ |
| Difference | −0.03 ± 2 | −0.6 ± 2 | 0.6 ± 2 | 0.006 ⁎ |
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