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J Am Coll Cardiol, 2007; 49:778-783, doi:10.1016/j.jacc.2006.05.081 (Published online 6 February 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: HEART FAILURE

Beta-Blocker Therapy Induces Ventricular Resynchronization in Dilated Cardiomyopathy With Narrow QRS Complex

Yasuhiko Takemoto, MD, PhD*,*, Takeshi Hozumi, MD, PhD, FACC*, Kenichi Sugioka, MD, PhD*, Yasuhiro Takagi, MD, PhD*, Yoshiki Matsumura, MD, PhD*, Minoru Yoshiyama, MD, PhD*, Theodore P. Abraham, MD, FACC{dagger} and Junichi Yoshikawa, MD, PhD, FACC{ddagger}

* Department of Internal Medicine and Cardiology, Osaka City University School of Medicine, Osaka, Japan
{dagger} Division of Cardiology, John Hopkins University, Baltimore, Maryland
{ddagger} Department of Cardiology, Osaka Ekisaikai Hospital, Osaka, Japan.

Manuscript received January 17, 2006; revised manuscript received April 19, 2006, accepted May 22, 2006.

* Reprint requests and correspondence to: Dr. Yasuhiko Takemoto, Department of Internal Medicine and Cardiology, Osaka City University School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan. (Email: yatakemoto{at}med.osaka-cu.ac.jp).


   Abstract
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 Abstract
Methods
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 Discussion
 References
 
OBJECTIVES: We sought to evaluate the effects of beta-blocker therapy on regional and global myocardial mechanics in addition to ventricular synchrony in patients with heart failure and normal QRS by using tissue Doppler and strain echocardiography.

BACKGROUND: It is unknown whether beta-blocker therapy can influence mechanical synchrony.

METHODS: Conventional and strain echocardiography were performed in 15 healthy age-matched volunteers and in 25 patients with idiopathic dilated cardiomyopathy (IDC). Of these, 15 IDC patients on standard heart failure therapy were studied prior to and at 1 and 6 months after initiation of carvedilol therapy and compared to the controls.

RESULTS: There was significant mechanical dyssynchrony in IDC compared with control patients. Patients placed on carvedilol demonstrated a significant decrease in the inferoseptal to lateral wall delay in peak strain (normalized to the R-R interval) between baseline and 1 month and between baseline and 6 months. Similarly, global time to peak segmental strain (455 ± 51 ms vs. 423 ± 59 ms, respectively, p = 0.02, and 455 ± 51 ms vs. 415 ± 50 ms, respectively, p = 0.01) and the coefficient of variation of the time to peak segmental strain decreased (17 ± 4% vs. 15 ± 5%, respectively, p = 0.02, and 17 ± 4% vs. 14 ± 5%, respectively, p = 0.03), from baseline to 1 month and between baseline and 6 months, respectively. Global strain significantly increased from baseline to 1 month (–8.2 ± 1.8 to –10.4 ± 3.9, respectively, p = 0.01) and between baseline and 6 months (–8.2 ± 1.8% to –12.0 ± 3.2%, respectively, p = 0.008). Improvements in left ventricular ejection fraction and reverse remodeling were coincident with reductions in mechanical dyssynchrony.

CONCLUSIONS: The use of carvedilol improves contractile function and dyssynchrony in heart failure patients with normal QRS.

Abbreviations and Acronyms
  CV = coefficient of variation
  CV{epsilon} = coefficient of variation of segmental {epsilon} values
  CVT{epsilon} = coefficient of variation of segmental T{epsilon}
  global {epsilon} = averaged segmental strain values over 12 segments
  global T{epsilon} = averaged segmental T{epsilon} values over 12 segments
  HF = heart failure
  HF-N = heart failure with narrow QRS complex (<120 ms)
  IDC = idiopathic dilated cardiomyopathy
  SE = tissue Doppler derived strain echocardiography
  segmental {epsilon} = peak systolic strain in a segment
  segmental T{epsilon} = time from the R-wave of the electrocardiogram trace to peak systolic strain in a particular segment
  TDE = tissue Doppler echocardiography

A significant proportion of patients with heart failure (HF) develop conduction abnormalities (1). Intraventricular dyssynchrony appears to play a major pathophysiologic role in HF, as suggested by the substantial clinical improvements observed after cardiac resynchronization therapy (CRT) through biventricular pacing (2,3). As a result, CRT has emerged as a promising treatment for medically refractory heart failure. Published data suggest that CRT improves patient symptom and quality of life, induces reverse remodeling, positively impacts neurohumoral pathways, and may improve outcomes and survival (4,5). The presence of significant intraventricular synchrony appears to predict a patient’s response to CRT (5,6).

All large CRT clinical trials primarily enrolled patients with significant prolongation of the QRS complex (>120 ms) (7,8). However, more recent data demonstrate that a proportion of HF patients with narrow QRS complexes also demonstrate significant intraventricular dyssynchrony as detected by tissue Doppler echocardiography (TDE) (9) There is a growing clinical conundrum as to whether patients with HF and narrow QRS complexes but significant ventricular dyssynchrony on TDE (heart failure + narrow QRS [HF-N]) would benefit from CRT. Decisions to treat HF-N patients with CRT devices have obvious clinical and economic implications.

Clinical trials have shown that medical therapy (e.g., beta-blockers) can induce morphologic reverse remodeling in patients with HF. However, it is unknown whether medical therapy can influence mechanical synchrony. Intuitively, beta-blocker therapy may worsen conduction abnormalities in patients and, therefore, dyssynchrony. Intraventricular synchrony is most commonly assessed using TDE, which is used to measure local tissue velocities and can accurately depict regional myocardial mechanical activity. Tissue Doppler-derived strain echocardiography (SE) depicts regional deformation and may be superior to TDE because it is less susceptible to translational and tethering artifacts (10). Accordingly, the present study sought to examine changes in ventricular function and mechanical synchrony using SE in HF-N patients receiving carvedilol therapy.


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Study group.   All patients and healthy volunteers provided informed consent, and the protocol was approved by the committee on clinical investigation of Osaka City University Institutional Review Board. We prospectively and consecutively enrolled patients with idiopathic dilated cardiomyopathy (IDC). Inclusion criteria were ejection fraction (EF) <40%, narrow QRS <120 ms, normal sinus rhythm, no significant coronary artery stenosis confirmed by coronary angiography, and no prior administration of beta-blocker therapy. We excluded patients with significant valvular heart disease, a history of cardiac surgery, pacemaker implantation, congenital heart disease, secondary cardiomyopathy, atrial fibrillation, and QRS width exceeding 120 ms. All patients were clinically stable and on stable medical therapy, including angiotensin-converting enzyme inhibitor or angiotensin II receptor blockades and diuretics. All medication doses were optimized before enrollment and remained unchanged during the study. Healthy volunteers were solicited via campus advertisements and were individuals with no cardiac history, who were not on any cardioactive medications (including carvedilol), and who had a normal screening echo-Doppler examination. Controls were age-matched such that there was one control for every patient.

Beta-blocker therapy.   Carvedilol was initiated after initial echocardiographic examination in 15 patients with IDC. The starting dose was 2.5 or 5 mg/day, which was titrated upwards to a target dose of 20 mg/day or maximum tolerated dose. The control group subjects did not receive any medications.

Echocardiography.   All patients and controls underwent standard, comprehensive 2-dimensional (2D) and Doppler echocardiography at enrollment. Additionally, 15 patients with IDC were studied at 1 and 6 months after the initiation of carvedilol therapy. Left ventricular (LV) end-diastolic volume, end-systolic volume, and EF (biplane Simpson’s formula) were determined. All patients underwent TDE and SE at the same time points as conventional echocardiography. All age-matched healthy volunteers underwent standard, comprehensive 2D and Doppler echocardiography, TDE, and SE at a single time point. All imaging was performed using a Vivid 7 ultrasound system (GE Ultrasound, Horten, Norway). Standard views were used for conventional echocardiography. For TDE and SE, single walls were imaged in 3 apical views, at high frame rates (170 to 200 frames/s) using a narrow sector angle with the wall parallel to the ultrasound beam (10). At least 3 consecutive beats were obtained, and the images were stored digitally for offline analysis. All TDE and SE parameters were analyzed per segment using a standard 12-segment (American Society of Echocardiography) model. A strain offset length of 8 mm was used for all measurements. Systolic strain tracings from 3 cardiac cycles were obtained of each segment and averaged to yield a final strain curve. Peak systolic strain (segmental {epsilon}) and time from the R-wave of the ECG trace to peak systolic strain (segmental T{epsilon}) were measured on the averaged strain curve of each segment. All segmental T{epsilon} values were corrected for the heart rate using Bazett’s formula to avoid the confounding influence of changes in heart rate during carvedilol therapy. Segmental {epsilon} values were averaged over the course of 12 segments to yield a global {epsilon} value (global {epsilon}). The coefficient of variation of segmental {epsilon} values (CV{epsilon}) was used as an index of heterogeneity of segmental mechanical contraction. The CV{epsilon} was obtained by dividing the standard deviation by the mean of segmental {epsilon} values. Segmental T{epsilon} values were averaged over the course of 12 segments to yield a global T{epsilon} value (global T{epsilon}). The coefficient of variation of segmental T{epsilon} (CVT{epsilon}) was used as a measure of intraventricular dyssynchrony. The CVT{epsilon} was calculated by dividing the standard deviation by the mean of segmental T{epsilon} values.

Statistics.   All values were expressed as mean ± SD. The Friedman test was used to compare the 3 time points, followed by the Wilcoxon signed-rank test in case of significance. A value of p < 0.05 was considered to indicate statistical significance. Simple comparison-wise p values derived from the Wilcoxon signed-rank test are reported in the tables and figures. Interobserver and intraobserver variability for both segmental T{epsilon} and segmental {epsilon} were measured by analysis of 4 randomly selected patients (144 segments) and 4 randomly selected healthy volunteers (48 segments) by 2 independent blinded observers. All results were compared by linear least-squares regression analysis. Limits-of-agreement analysis by the methods of Bland and Altman also was performed.


   Results
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Discussion
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We enrolled 25 patients with IDC and 15 healthy controls. Of these, 19 patients were enrolled consecutively, whereas 10 additional patients were enrolled later. Four patients did not complete the study protocol (1 died during the follow-up, 1 developed left bundle branch block during the follow-up, and 2 were lost to follow-up). Therefore, cross-sectional data were available in 25 patients with IDC and 15 control patients. Longitudinal data were available from 15 patients with IDC. Baseline characteristics of the patients with IDC who were followed longitudinally are given in Table 1. The mean maintenance dose of carvedilol was 11 ± 6 mg/day.


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  		Table 1. Baseline Characteristics
 
Hemodynamic and echocardiographic parameters.   Hemodynamic and echocardiographic data are summarized in Table 2. There was no significant change in systolic and diastolic blood pressures during the study. There was significant decrease in heart rates from baseline to 1 month (84 ± 12 beats/min vs. 72 ± 9 beats/min, respectively, p = 0.001) with no further significant change at 6 months.


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  		Table 2. Hemodynamic and Echocardiographic Parameters
 
There were no significant reductions in LV end-diastolic and end-systolic volumes at 1 month. However, there were significant reductions in end-diastolic (193 ± 70 ml vs. 156 ± 68 ml, respectively, p = 0.008) and end-systolic volumes (140 ± 58 ml vs. 105 ± 65 ml, respectively, p = 0.006) between baseline and 6 months.

Although there was a nonsignificant trend toward an increase in left ventricular ejection fraction between baseline and 1 month (28 ± 6% vs. 31 ± 7%, p = 0.06), there was a significant increase in left ventricular ejection fraction between baseline and 6 months (28 ± 6% vs. 37 ± 10%, respectively, p = 0.004).

Strain echocardiography.   There was significant dyssynchrony in the IDC patients with narrow QRS complexes (n = 25) compared with the normal controls (n = 15). Global T{epsilon} was 457 ± 56 ms versus 348 ± 24 ms (p < 0.0001), CV segmental T{epsilon} was 18 ± 4% versus 7 ± 3% (p < 0.0001), global {epsilon} was –8.1 ± 1.8% versus –18.5 ± 1.3% (p < 0.0001), and CV segmental {epsilon} was 43 ± 10% versus 14 ± 3% (p < 0.0001), respectively (IDC vs. controls). These data confirm the presence of dyssynchrony in IDC patients with narrow QRS complex compared with normal healthy volunteers.

Figure 1 displays representative myocardial strains at the LV midinferoseptal and midlateral segments at baseline, 1 month, and 6 months. There was a significant decrease in the inferoseptal to lateral wall delay in segmental T{epsilon} between baseline and 1 month (103 ± 51 ms vs. 70 ± 45 ms, respectively, p = 0.02) and baseline and 6 months (103 ± 51 ms vs. 51 ± 46 ms, respectively, p = 0.002).


Figure 1
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  		Figure 1 Representative Traces of Myocardial Strains

(Top) Myocardial strains of the left ventricular midinferoseptal segment: left panels = baseline; middle panels = 1 month; right panels = 6 months. (Bottom) Myocardial strains of the left ventricular midlateral segment. Inferoseptal to lateral wall delay in time from electrocardiographic peak R wave to peak systolic strain was 83 ms at baseline, –2 ms at 1 month, and –3 ms at 6 months.

 
Table 3 demonstrates EF and SE parameters in healthy volunteers and the temporal changes in patients with IDC. The EF and all SE parameters in healthy volunteers were significantly different from those in patients with IDC at baseline, 1 month, and 6 months. In patients with IDC, there was a significant decrease in global T{epsilon} from baseline to 1 month (455 ± 51 ms vs. 423 ± 59 ms, respectively, p = 0.02), and between baseline and 6 months (455 ± 51 ms vs. 415 ± 50 ms, respectively, p = 0.01). There were similar decreases in CV segmental T{epsilon} between baseline and 1 month (17 ± 4% vs. 15 ± 5%, respectively, p = 0.02) and between baseline and 6 months (17 ± 4% vs. 14 ± 5%, respectively, p = 0.03).


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  		Table 3. Ejection Fraction and Strain Echocardiographic Data
 
Global {epsilon} was significantly reduced in all subjects at baseline (mean global {epsilon} = –8.2 ± 1.8%). There was a significant increase in global {epsilon} from baseline to 1 month (–8.2 ± 1.8% to 10.4 ± 3.9%, respectively, p = 0.01) and between baseline and 6 months (–8.2 ± 1.8% to 12.0 ± 3.2%, respectively, p = 0.008). In contrast, there was no significant change in CV segmental {epsilon} between baseline and 1 month (44 ± 12% vs. 47 ± 22%, respectively, p = 0.38). However, CV segmental {epsilon} decreased significantly from baseline/1 month to 6 months (44 ± 12%/47± 22% vs. 33 ± 15%, respectively, p = 0.03). Table 3 demonstrates temporal changes of EF, global T{epsilon}, CV segmental T{epsilon}, global {epsilon}, and CV segmental {epsilon}. Parallel significant temporal changes can be seen only between EF and CV segmental {epsilon}, not between EF and CV segmental T{epsilon} or global {epsilon}.The normalization for heart rate was performed using Bazett’s formula. In the absence of normalization, global T{epsilon} were as follows: volunteers at enrollment, 339 ± 24 ms; IDC patients at baseline, 386 ± 38 ms; IDC patients at 1 month, 388 ± 43 ms; and IDC patients at 6 months, 386 ± 45 ms. Global T{epsilon} was significantly lower in volunteers at enrollment compared with IDC patients at baseline (p = 0.0005), at 1 month (p = 0.0015), and at 6 months (p = 0.0024), respectively. Global T{epsilon} was similar between IDC patients at all 3 time points. Coefficient of variation segmental T{epsilon} was as follows: volunteers at enrollment, 7 ± 3%; IDC patients at baseline, 17 ± 4%; IDC patients at 1 month, 15 ± 5%; and IDC patients at 6 months, 14 ± 5%. Coefficient of variation segmental T{epsilon} was significantly lower in volunteers at enrollment compared with IDC patients at baseline (p < 0.0001), at 1 month (p = 0.0001), and at 6 months (p = 0.0010), respectively. In patients with IDC, there was a significant decrease in CV segmental T{epsilon} from baseline to 1 month (17 ± 4% vs. 15 ± 5%, respectively, p = 0.02), and from baseline to 6 months (17 ± 4% vs. 14 ± 5%, respectively, p = 0.03).

Intraobserver and interobserver variability for segmental T{epsilon} measurement was 2.9% and 6.9%, respectively. Intraobserver and interobserver variability for segmental {epsilon} was 8.8% and 12.3%, respectively.


   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
Our data demonstrate that beta-blocker therapy induces significant reductions in intraventricular dyssynchrony in dilated cardiomyopathy patients with heart failure and normal QRS. Beta-blocker therapy is associated with an early (1 month) increase in regional systolic function (increased global {epsilon}) and a delayed decrease in mechanical dyssynchrony (decreased CV{epsilon}). Improvements in LVEF and reverse remodeling are coincident with reductions in mechanical dyssynchrony. Reduction in ventricular dyssynchrony may be one of the mechanisms underlying the beneficial effects of beta-blockers in HF.

Intraventricular and interventricular dyssynchrony have emerged as important mechanisms contributing to the progression of heart failure and ventricular remodeling (2,3). Their emergence has resulted in CRT becoming a significant alternative in HF refractory to medical therapy in patients with evidence of abnormal conduction. Beta-blockers such as carvedilol are a critical component of HF therapy. However, the interaction between beta-blockers and dyssynchrony is uncertain. Furthermore, the effects of beta-blocker therapy on regional and global cardiac mechanics have not been previously examined. Carvedilol therapy has favorable effects on ventricular function, ventricular remodeling, heart failure symptoms, morbidity, and mortality (11–15). Although the precise mechanisms underlying these favorable effects have not been fully clarified at the whole heart level, several possible mechanisms include reduction of heart rate and/or afterload (16), alleviation of adverse neurohormonal effects (17), and antiapoptotic effects (18). To define the effects of carvedilol therapy on cardiac mechanics and dyssynchrony, we used tissue Doppler-derived strain echocardiography to interrogate regional and global myocardial function.

Tissue Doppler echocardiography and TDE-derived SE depict regional displacement and deformation (19,20). Both techniques have been extensively validated in the experimental and clinical setting (21–23). Because mechanical synchrony cannot be assessed adequately via conventional echocardiography, TDE and SE have become the mainstays of dyssynchrony interrogation. Detailed descriptions of SE have been previously published (20). Although most data regarding cardiac dyssynchrony have been generated using TDE, SE offers some advantages. Strain imaging is less susceptible to translational motion and tethering artifacts and may be useful in subjects with extensive wall motion abnormalities. Moreover, SE is superior to TDE in regional function analysis and was therefore more appropriate to accomplish our study objectives (10).

Our data demonstrate that carvedilol therapy significantly increases regional and global contractility as evidenced by an increase in {epsilon} and EF. Our data also clarify the changes in regional and global cardiac mechanics that potentially underlie the improvements in cardiac function seen from carvedilol therapy. Early after initiation of carvedilol therapy there appears to be an increase in regional contractility. These regional changes in systolic function may be explained by previously demonstrated restoration of the biological properties of the cardiac myocyte by carvedilol, including the reversal of high-energy phosphate production and normalization of calcium handling (24–27). Improvement of impaired coronary flow reserve by carvedilol may also contribute to the recovery of LV function (28).

However, it appears that the early increments in local contractility do not translate into an increment in global function, as seen by the absence of a significant change in EF. On the other hand, an improvement in intraventricular synchrony, that occurs several months later, is associated with an increase in EF. The increase in EF and reduction in dyssynchrony is coincident with echocardiographic evidence of reverse remodeling. The coordinated LV contraction resulting in improved chamber efficiency and reduced myocardial energy consumption observed in CRT also may underlie the global LV function improvements found with the use of carvedilol (29,30). Our data concerning resynchronization and reverse remodeling are concordant with those reported from CRT studies (4,5).

Study limitations.   We excluded patients with ischemic cardiomyopathy. The effects of beta-blockers may be significantly different between patients with IDC and with ischemic cardiomyopathy. We only included IDC patients with QRS width <120 ms in this study. The effects of beta-blockers on dyssynchrony may be different in patients with more significant conduction disease (e.g., QRS >120 ms) and in patients with ischemia and/or significant myocardial scar.

Conclusions.   Beta-blocker therapy stimulates increments in local contractility and reduction of intraventricular dyssynchrony. To our knowledge, this is the first report of cardiac resynchronization by medical therapy. Increased regional systolic function followed by cardiac resynchronization potentially underlies the beneficial effects of beta-blockers in heart failure.


   References
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 Abstract
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 References
 

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