Author + information
- Received May 8, 2006
- Revision received July 14, 2006
- Accepted July 17, 2006
- Published online December 5, 2006.
- Cheuk-Man Yu, MD, FRCP⁎,⁎ (, )
- Yat-Sun Chan, FHKAM⁎,
- Qing Zhang, MM⁎,
- Gabriel W.K. Yip, MRCP⁎,
- Chi-Kin Chan, FHKAM†,
- Leo C.C. Kum, MRCP⁎,
- LiWen Wu, BM⁎,
- Alex Pui-Wai Lee, MRCP⁎,
- Yat-Yin Lam, MRCP⁎ and
- Jeffrey Wing-Hong Fung, FHKAM⁎
- ↵⁎Reprint requests and correspondence:
Prof. Cheuk-Man Yu, Division of Cardiology, S. H. Ho Cardiovascular and Stroke Centre, Institute of Vascular Medicine, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
Objectives This study was designed to evaluate the role of cardiac resynchronization therapy (CRT) in heart failure (HF) patients with narrow QRS complexes (<120 ms) and echocardiographic evidence of mechanical asynchrony.
Background Cardiac resynchronization therapy is currently recommended to advanced HF patients with prolonged QRS duration. Echocardiographic assessment of systolic mechanical asynchrony has been proven useful to predict a favorable response after CRT.
Methods A total of 102 HF patients with New York Heart Association (NYHA) functional class III or IV were enrolled. Among them, 51 had wide QRS (>120 ms) and 51 had narrow QRS (<120 ms). Tissue Doppler imaging (TDI) was employed to select patients with systolic asynchrony (increased asynchrony index) in the narrow-QRS group. Clinical and echocardiographic assessments were performed at baseline and 3 months after CRT.
Results There was a significant reduction of left ventricular (LV) end-systolic volume in both narrow (122 ± 42 cc vs. 103 ± 47 cc, p < 0.001) and wide (148 ± 74 cc vs. 112 ± 64 cc, p < 0.001) QRS groups. Improvement of NYHA functional class (both p < 0.001), maximal exercise capacity (both p < 0.05), 6-min hall-walk distance (both p < 0.01), ejection fraction (both p < 0.001), and mitral regurgitation (both p < 0.005) was also observed. In both groups, the degree of baseline mechanical asynchrony determined LV reverse remodeling to a similar extent, as shown by the superimposed regression lines. Withholding CRT for 4 weeks resulted in loss of echocardiographic benefits.
Conclusions Cardiac resynchronization therapy for HF patients with narrow QRS complexes and coexisting mechanical asynchrony by TDI results in LV reverse remodeling and improvement of clinical status. The amplitude of benefit is similar to the wide-QRS group provided that similar extent of systolic asynchrony is selected.
Cardiac resynchronization therapy (CRT) is an established therapy for patients with chronic heart failure (HF) with wide QRS complexes (1–3) . Left ventricular (LV) reverse remodeling is an objective structural end point that heralds improved long-term survival (4). However, about 30% to 40% of patients with wide QRS do not respond to the therapy (1,4–6). Echocardiographic assessment of systolic mechanical asynchrony was found useful to predict a favorable LV reverse remodeling response and therefore is a potentially important adjunctive tool for selecting appropriate patients for CRT (5,6).
Previous studies have shown that systolic asynchrony was present in 27% to 43% of HF patients with narrow QRS complexes (defined as <120 ms) (7,8). Therefore, CRT may have therapeutic potential to those with narrow QRS complexes and systolic asynchrony by echocardiography. The current study: 1) sought to determine whether CRT induces LV reverse remodeling and improves clinical status in patients with narrow QRS complexes who had coexisting systolic asynchrony by echocardiography, and 2) compared its efficacy with that in patients with wide QRS complexes. The effect of withholding CRT was also examined.
This study consisted of 102 optimally treated HF patients (mean age: 65 ± 12 years, 75% men) in New York Heart Association (NYHA) functional class III (n = 87) or IV (n = 15) who had an ejection fraction <40%, received CRT, and were followed up for at least 3 months. There were 51 patients with QRS duration <120 ms (narrow-QRS group) with predefined systolic asynchrony by echocardiography. The wide-QRS group consisted of 51 patients with QRS duration >120 ms with conventional electrocardiographic selection criteria alone for CRT. All patients received a biventricular pacemaker (Guidant Inc., St. Paul, Minnesota, or Medtronic Inc., Minneapolis, Minnesota). Serial clinical assessments and echocardiographic examinations were performed before and 3 months after CRT as well as after withholding pacing for 4 weeks. Clinical assessments included NYHA functional class, 6-min hall-walk test, Minnesota Living With Heart Failure Questionnaire for quality of life, and maximal metabolic equivalent achieved on treadmill test by Chronotropic Assessment Exercise Protocol (9). This study protocol was approved by our local ethics committee, and written informed consent was obtained from all patients. The primary end point was LV reverse remodeling as reflected by a decrease in LV end-systolic volume. Secondary end points included clinical parameters and change in LV ejection fraction. To detect a 30-cc or 20% reduction in LV end-systolic volume with an SD of measurement of 55 cc and a statistical power of 80%, 27 patients in each group were needed to allow for 2-sided alpha of 0.05.
Echocardiographic assessment of cardiac function
Standard echocardiography was performed (Vivid 7, Vingmed-General Electric, Horten, Norway). The LV volumes and ejection fraction were assessed by biplane Simpson’s equation (10). The LV +dp/dt, mitral regurgitation, myocardial performance index, and sphericity index were measured (5).
Tissue Doppler imaging (TDI) was performed using apical 4-chamber, 2-chamber, and long-axis views for long-axis motion of the LV (EchoPac-PC [BT-05], Vingmed-General Electric, Horten, Norway) (6,10,11). Systolic asynchrony was assessed by calculating the standard deviation of the time to peak systolic velocity in ejection phase of the 12 LV segments (asynchrony index) (5,6,11), and the cutoff value was 32.6 ms. It was predetermined that about one-half of the patients enrolled in the narrow-QRS group had significant systolic asynchrony (asynchrony index ≥32.6 ms) and the other half had no significant asynchrony (asynchrony index 15 to <32.6 ms). This would provide further information to examine the importance of before-treatment systolic asynchrony in predicting a favorable response and allow parallel comparison with the wide-QRS group.
The comparison of parametric variables before and after CRT was performed by paired-sample ttest. The comparison of clinical and echocardiographic parameters between wide- and narrow-QRS groups was performed by unpaired ttest or Pearson chi-square test where appropriate. Pearson correlation analysis was used to examine the relationship between before-pacing systolic asynchrony and the change of LV end-systolic volume after CRT. Stepwise multivariate regression analysis was employed to examine predictors of LV reverse remodeling using the change of LV end-systolic volume as the dependent covariate. Receiver-operating characteristic (ROC) curves were analyzed for asynchrony index in predicting LV reverse remodeling. The sensitivity and specificity of best-performing cutoff values were examined in both groups. Data were expressed as mean values ± SD. A p value <0.05 was considered statistically significant.
There was no difference in age, gender, or etiologies of HF between the narrow- and wide-QRS groups (Table 1).However, the narrow-QRS group had less severe clinical status and smaller LV volume at baseline. There was no difference in optimized atrioventricular interval (102 ± 30 ms vs. 98 ± 34 ms, p = NS).
LV function and reverse remodeling
Left ventricular reverse remodeling, together with improvement in myocardial performance index, mitral regurgitation, and diastolic filling time, was evident in both groups (Tables 2 and 3).⇓⇓There was no difference between the 2 groups in improvement of echocardiographic parameters, except that the reduction of LV end-diastolic volume was greater in the wide-QRS group (Table 4).When pacing was withheld for 4 weeks, the echocardiographic benefits of CRT disappeared in both groups (Tables 2 and 3).
In both groups, CRT resulted in significant improvement in most clinical parameters, except for quality of life (Tables 2 and 3). The amplitude of improvement in these clinical parameters was similar, with the exception of quality of life, which was improved only in the wide-QRS group (p < 0.001) (Table 4). When pacing was withheld for 4 weeks, there was no significant change in clinical parameters in both groups (Tables 2 and 3).
Comparison of relationship between changes in LV systolic asynchrony and the degree of reverse remodeling in narrow- and wide-QRS groups
There was significant correlation between before-pacing systolic asynchrony index and changes in LV end-systolic volume in both groups, as shown in Figure 1.Furthermore, the regression lines of these 2 groups superimpose on each other with nearly identical slopes (narrow: −0.46 ± 0.09 vs. wide: −0.42 ± 0.06) and Y-intercept (narrow: 28.10 ± 2.15 ms vs. wide: 28.00 ± 1.95 ms).
The prevalence of “responders” was 62.7% (32 of 51) in the wide-QRS group and 45.1% (23 of 51) in the narrow-QRS group (chi-square = 3.20, p = 0.07), as defined by a reduction of LV end-systolic volume >15% (5,10,11). The areas under ROC curves were good for both narrow- and wide-QRS groups (Fig. 2).From the shoulders of the ROC curves, the cutoff values of asynchrony index for predicting LV reverse remodeling were the same (i.e., 32.7 ms), with high sensitivity and specificity. Figure 3is an example of a CRT responder.
By multivariate analysis, Ts-SD was the only independent predictor of LV reverse remodeling in both narrow- (beta = −0.81, confidence interval = −0.49 to −1.12, p < 0.001) and wide-QRS groups (beta = −1.17, confidence interval = −0.75 to −1.59, p < 0.001).
Improvement of cardiac function in narrow QRS group stratified by asynchrony index
Twenty-seven patients in the narrow-QRS group had significant systolic asynchrony. There was no difference in baseline clinical and echocardiographic characteristics between those with and without significant asynchrony. However, those with significant asynchrony had a greater extent of LV reverse remodeling than those without (all p < 0.001) (Fig. 4).
This study revealed that CRT may be beneficial in selected patients with narrow QRS complexes. It illustrated that those patients with mechanical asynchrony detected by TDI had improvement in symptoms, exercise capacity and, most importantly, LV systolic function with reverse remodeling after CRT. Moreover, the echocardiographic benefits by CRT disappeared when pacing was withheld, further ascertaining the pacing-dependent nature of CRT benefits. Interestingly, for a similar extent of before-pacing systolic asynchrony, the degree of cardiac improvement is very similar to those with wide QRS complexes. This was corroborated by the finding that the improvement of cardiac structure was more dramatic in those with significant mechanical asynchrony among the narrow-QRS group.
Role of CRT for HF patients with narrow QRS complexes
Cardiac resynchronization therapy is an established therapy for HF patients with wide QRS complexes (>120 ms), which signify the presence of LV electromechanical abnormality. However, previous studies observed that only 25% of HF patients had wide QRS complexes (12,13). On the other hand, mechanical asynchrony detected by echocardiography is present in up to 43% of HF patients with narrow QRS duration (<120 ms) (7,8,14). Therefore, the current selection criteria may have excluded a large proportion of patients who may potentially benefit from CRT (15). It is thus worthwhile to examine the role of CRT for those with narrow QRS complexes and systolic asynchrony.
In the wide-QRS group, CRT response is predicted by the degree of systolic asynchrony (5,16). This suggests that the presence of mechanical asynchrony rather than wide QRS is a major determinant of CRT benefits. The potential role of CRT in narrow-QRS patients was evaluated in 2 studies (17,18). Achilli et al. (17) examined 14 HF patients with narrow QRS complexes. Although there was improvement in clinical parameters and LV ejection fraction, degree of LV reverse remodeling was not measured (17). Turner et al. (18) reported an insignificant increase in ejection fraction in 8 patients with narrow QRS complex after CRT. However, both studies were limited by a small sample size. In particular, the latter study did not examine the presence of before-pacing systolic asynchrony and therefore resulted in the selection of patients with only mild to moderate systolic asynchrony when compared with the wide-QRS group (18).
The present study is the largest that examined comprehensively the clinical and echocardiographic benefits of CRT in HF patients with narrow QRS complexes. In particular, we examined the presence of systolic asynchrony prospectively by the use of validated parameters. A close relationship between systolic asynchrony and the degree of reverse remodeling was observed in these patients. Intriguingly, the degree of LV reverse remodeling was similar between the wide- and narrow-QRS groups if the extent of mechanical asynchrony was similar. This is illustrated by the nearly superimposed regression lines with nearly identical slopes as well as X- and Y-intercepts in both groups (Fig. 1). Therefore, this study reemphasized the importance of screening for intraventricular systolic asynchrony in narrow-QRS patients. Furthermore, the cutoff values for the asynchrony index derived from the ROC curves to predict a favorable reverse remodeling response were identical for both groups (32.7 ms), which is nearly identical to the value derived from a control population (32.6 ms) (12). This confirms the internal consistency and usefulness of employing the asynchrony index as a screening tool to detect systolic asynchrony irrespective of QRS duration.
This study has a relatively small sample size and is a single-center experience. However, the sample size has adequate power to examine the occurrence of LV reverse remodeling as the primary end point and is the largest study of narrow-QRS patients to date. The result of the present study will also provide valuable reference information for the consideration of large, controlled, multicenter trials of CRT in narrow-QRS patient groups, which it is hoped will extend CRT benefits to a wider spectrum of HF patients. Although the use of 3 apical views to calculate asynchrony index appears to be complex, comprehensive assessment of underlying mechanical asynchrony is necessary to select the potential responders, as shown in the current study.
This study illustrated that CRT benefits HF patients with narrow QRS complexes who had mechanical asynchrony as demonstrated by TDI. The extent of LV reverse remodeling after CRT benefit is similar to those with wide QRS complexes. Furthermore, the same cutoff value of asynchrony index appears useful to identify significant systolic asynchrony in both wide- and narrow-QRS groups.
This study was jointly supported by a research grant from Guidant Inc. and a direct grant from the Chinese University of Hong Kong (Ref 2003.1.061).
- Abbreviations and Acronyms
- cardiac resynchronization therapy
- heart failure
- left ventricular
- New York Heart Association
- receiver-operating characteristic
- tissue Doppler imaging
- Received May 8, 2006.
- Revision received July 14, 2006.
- Accepted July 17, 2006.
- American College of Cardiology Foundation
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