Abstract

Aims

To assess long-term effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) dyssynchrony and contractile function, by two-dimensional speckle-tracking echocardiography, compared with implantable cardioverter defibrillator (ICD) only in MADIT-CRT.

Methods and results

We studied 761 patients in New York Heart Association I/II, ejection fraction ≤30%, and QRS ≥130 ms [n = 434, CRT-defibrillator (CRT-D), n = 327, ICD] with echocardiographic studies available at baseline and 12 months. Dyssynchrony was determined as the standard deviation of time to peak transverse strain between 12 segments of apical four- and two-chamber views, and contractile function as global longitudinal strain (GLS) by averaging longitudinal strain over these 12 segments. We compared changes in LV dyssynchrony and contractile function between treatment groups and assessed relationships between these changes over the first year and subsequent outcomes (median post 1-year follow-up = 14.9 months). Mean changes in LV dyssynchrony and contractile function measured by GLS in the overall population were, respectively, −29 ± 83 ms and −1 ± 2.9%. However, both LV dyssynchrony (CRT-D: −47 ± 83 ms vs. ICD: −6 ± 76 ms, P < 0.001) and contractile function (CRT-D: −1.4 ± 3.1% vs. ICD: −0.4 ± 2.5%, P < 0.001) improved to a greater extent in the CRT-D group compared with the ICD-only group. A greater improvement in dyssynchrony and contractile function at 1 year was associated with lower rates of the subsequent primary outcome of death or heart failure, adjusting for baseline dyssynchrony and contractile function, treatment arm, ischaemic status, and change in LV end-systolic volume. Each 20 ms decrease in LV dyssynchrony was associated with a 7% reduction in the primary outcome (P = 0.047); each 1% improvement in GLS over the 12-month period was associated with a 24% reduction in the primary outcome (P < 0.001).

Conclusion

Cardiac resynchronization therapy resulted in a significant improvement in both LV dyssynchrony and contractile function measured by GLS compared with ICD only and these improvements were associated with better subsequent outcomes.

Introduction

Cardiac resynchronization therapy (CRT) has been shown to reduce the risk of death or heart failure (HF), and improve functional status and left ventricular (LV) function in patients with advanced HF, LV dysfunction, and wide QRS.1–3 More recently, the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE), and Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) trials have broadened CRT indications to mildly symptomatic patients.4–6 Previous studies have demonstrated that improvement in LV size and performance may be among the most important contributors to improved outcomes in patients receiving CRT.7–10 However, response to CRT varies significantly among selected individuals and ∼30% of the patients do not appear to improve clinically or exhibit favourable echocardiographic remodelling. Recent studies have suggested that both LV mechanical dyssynchrony and contractile function are important determinants of CRT benefit.11–13 Yet, it remains unclear to what extent improvement in LV dyssynchrony and/or LV contractile function translates into better clinical responses after CRT.

Over the past years, measures of LV synchrony and contractile function by speckle tracking appeared to be more robust than measures utilizing Doppler-based techniques.14–16 We thus utilized speckle-tracking strain analysis, which permits the assessment of both LV dyssynchrony and contractile function in a reproducible and angle-independent manner to test the hypothesis that CRT restores LV performance by improving synchrony and contractile function and to assess the relationship between these changes over the first year of therapy and subsequent outcomes.

Methods

Patient population

MADIT-CRT randomized patients with mildly symptomatic HF [New York Heart Association (NYHA) class I or II if ischaemic, NYHA class II if non-ischaemic], ejection fraction (EF) ≤30%, and QRS ≥ 130 ms. A total of 1820 patients were enrolled from December 2004 through April 2008 at 110 centres in the USA, Canada, and Europe. Patients were randomly assigned in a 3:2 ratio to receive CRT-defibrillator (CRT-D) therapy or implantable cardioverter defibrillator (ICD)-only therapy. Additional details regarding inclusion and exclusion criteria have been published previously.4,17 Stratification included clinical centre and ischaemic status.

Echocardiograms were obtained according to a study protocol at baseline, just prior to device implantation, and at 1 year. The first 201 patients had undergone follow-up echocardiography with the device turned off as requested by the Food and Drug Administration. These patients are not included in this analysis. The protocol was amended so that follow-up studies would be performed with the device on. A total of 761 patients (ICD, n = 327; CRT, n = 434) had paired echocardiograms with device turned on and image quality sufficient for dyssynchrony and strain analysis based on B-mode speckle-tracking methods. Patients with non-DICOM images and frame rate <30 Hz, missing view, or insufficient two-dimensional (2D) image quality (i.e. contrast application, endocardial dropout, out of plane images) were excluded from the analysis (Figure 1).

Figure 1

Feasibility of speckle-tracking analysis in consecutive patients.

Figure 1

Feasibility of speckle-tracking analysis in consecutive patients.

Echocardiographic analysis

Standard echocardiographic parameters, including LV volumes and EF, were analysed with an offline analysis workstation as described previously.7 Echocardiographic response was defined as a 15% decrease in LV end-diastolic volume. Left ventricular dyssynchrony and contractile function indices were measured using B-mode speckle-tracking software (algorithm based on velocity vector imaging, Amid, Cardiac Performance Imaging, TomTec, 1.0) that circumvents angle dependency and identifies cardiac motion by tracking multiple reference points. The endocardial borders were traced in the end-systolic frame of the 2D images from the apical four- and two-chamber views. Speckles were tracked frame-by-frame throughout the LV myocardium over the course of two or more cardiac cycles; basal, mid, and apical regions of interest were created. Segments that failed to track were manually adjusted. If two or more segments could not be tracked, the measurements were considered as unreliable and the study was excluded from the analysis. Tracings in each view were performed by a single investigator blinded to treatment assignment, clinical/demographical data, and clinical outcomes.

Mechanical dyssynchrony of the LV was determined as the standard deviation of regional time-to-peak transverse strain (in ms), measured during systole, across all 12 anatomic wall segments of the apical four- and two-chambers views.18–20 Of note, both transverse and radial strain assess myocardial thickening in the same direction but the nomenclature is different based on which the view is utilized (transverse strain is the preferred term when acquired from the apical views). Global longitudinal strain (GLS), a detailed measure of LV contractile function, was calculated as the average of peak longitudinal strain across the 12 segments of the apical four- and two-chamber views.21Figure 2 illustrates changes in LV dyssynchrony and contractile function measured by GLS in a CRT-D patient. Intra- and inter-observer variability was assessed in 75 randomly selected patients with a broad range of LVEF. The coefficients of variation were 13.8 and 15.4% for time-to-peak transverse strain and 7.7 and 8.0% for longitudinal strain, respectively.

Figure 2

Two-dimensional speckle-tracking imaging in the apical four-chamber view in a patient before (left panel) and after cardiac resynchronization therapy-defibrillator implantation (right panel). Upper curves represent transverse strain curves, which were used to measure left ventricular dyssynchrony and lower curves represent longitudinal strain that were used to measure contractile function. Improvement in left ventricular dyssynchrony and left ventricular contractile function was shown at follow-up.

Figure 2

Two-dimensional speckle-tracking imaging in the apical four-chamber view in a patient before (left panel) and after cardiac resynchronization therapy-defibrillator implantation (right panel). Upper curves represent transverse strain curves, which were used to measure left ventricular dyssynchrony and lower curves represent longitudinal strain that were used to measure contractile function. Improvement in left ventricular dyssynchrony and left ventricular contractile function was shown at follow-up.

Outcomes

The primary endpoint was death from any cause or a non-fatal HF event, whichever came first. The diagnosis of HF required signs and symptoms consistent with congestive HF that was responsive to intravenous decongestive therapy on an outpatient basis or an augmented decongestive regimen with oral or intravenous medications during an in-hospital stay. Adjudication of the endpoints was carried out by an independent endpoint committee that was unaware of study group assignments, as described previously.17

Statistical analysis

Changes in LV dyssynchrony and contractile function by GLS had an approximate normal distribution and were used as continuous variables in all our models. Continuous variables were expressed as mean ± SD. We categorized the patients in quartiles according to the change in dyssynchrony and contractile function measurements and applied trend tests across ordered groups to illustrate the relationship between changes in LV dyssynchrony, contractile function, demographic data, and other measures. Patients were also divided into four groups according to their median values of change in dyssynchrony (more improvement in dyssynchrony: more negative than −30 ms; less improvement in dyssynchrony: less negative than −30 ms) and change in GLS after 12 months (>−0.8%, <−0.8%). As a more negative GLS indicates better contractile function, more negative differences in strain numbers between baseline and 1-year assessments were indicative of a greater improvement in contractile function. Pearson's correlation coefficient was used to test the relationship between continuous variables. Between-treatment-group differences in the change in LV dyssynchrony and contractile function measured by GLS from baseline to 12 months were assessed in analysis of covariance adjusting for treatment group, ischaemic aetiology, and baseline measure of strain or dyssynchrony. The effect of treatment on LV dyssynchrony and contractile function measured by GLS was compared in the subgroups of male or female, ischaemic status, QRS width greater or less than 150 ms, and the presence of left bundle branch block (LBBB), and the interaction between subgroup and treatment effect with respect to change in dyssynchrony or strain was assessed.

The relationship between changes in LV dyssynchrony and contractile function measured by GLS from baseline to follow-up and the primary outcome subsequent to the 1-year echocardiogram (landmark analysis) was assessed using Cox's proportional hazards methods, either adjusting for baseline LV dyssynchrony or LV contractile function measured by GLS, treatment group, ischaemic status, and change in LV end-systolic volume (LVESV), or in a more fully adjusted model, including baseline strain or dyssynchrony, treatment group, age, gender, QRS duration, LBBB, ischaemic status change in LVESV, and change in LVEF. The adjustment model included the most powerful predictors for primary outcome, which were identified from the overall MADIT-CRT study using stepwise selection and elimination and forced in variables considered to be clinically relevant. In the landmark analysis, we excluded patients with events (n = 45) prior to the 1-year echocardiogram.

All analyses were performed using STATA version 10 (Stata Corporation, TX, USA). For all analyses, all tests were two-sided and a P-value of <0.05 was considered statistically significant.

Results

Baseline characteristics

A total of 761 patients (n = 434, CRT-D; n = 327, ICD) had paired echocardiographic data available with adequate image quality for 2D speckle-tracking analysis. Baseline characteristics of the patients included in this analysis were comparable to the remainder of the MADIT-CRT study with respect to age, gender, NYHA functional class, ischaemic status, QRS width and morphology, systolic and diastolic blood pressure, estimated glomerular filtration rate, LV end-diastolic volume, LVESV, and medication. However, our cohort had a lower rate of history of diabetes mellitus (27 vs. 33%, P = 0.039). Baseline characteristics and the use of various cardiac medications at enrolment were also similar in the two treatment arms. However, CRT-D patients had a slightly higher systolic and diastolic blood pressure compared with ICD-only patients (124 ± 17 vs. 121 ± 19 mmHg, P = 0.01 and 72 ± 10 vs. 71 ± 11 mmHg, P = 0.01).

Change in contractile function and dyssynchrony in implantable cardioverter defibrillator-only and cardiac resynchronization therapy-defibrillator groups

The greatest improvement in LV dyssynchrony was associated with younger age, female, the presence of LBBB, echo-response defined as a 15% decrease in LV end-diastolic volume, the presence of a CRT-D device, a lower event rate, and inversely related to ischaemic status (Table 1). The same trends were noted for the greatest improvement in LV contractile function measured by GLS (Table 1). We also noted a trend (P = 0.049) for patients with wide QRS to have a greater improvement in dyssynchrony. This relationship was not observed across quartiles of change in GLS.

Table 1

Baseline characteristics by quartiles of change in transverse dyssynchrony and change in global longitudinal strain in 761 patients

graphic 
graphic 

NYHA, New York Heart Association; RBBB, right bundle branch block; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume.

Mean changes in LV dyssynchrony and contractile function measured by GLS in the overall population were, respectively, −29 ± 83 ms and −1 ± 2.9%. However, both LV dyssynchrony (CRT-D: −47 ± 83 ms vs. ICD: −6 ± 76 ms, P < 0.001) and contractile function measured by GLS (CRT-D: −1.4 ± 3.1% vs. ICD: −0.4 ± 2.5%, P < 0.001) improved to a greater extent in the CRT-D group compared with the ICD-only group (Figure 3). In our population, a large variation in the extent of LV resynchronization and improvement in LV contractile function was observed: 72% of the patients in the CRT-D group vs. 53% in the ICD-only group revealed some degree of reduction in LV dyssynchrony and 78% of the patients in the CRT-D group vs. 56% in the ICD-only group improved their LV strain to some extent. Furthermore, within the treatment group, change in LV contractile function measured by GLS correlated weakly with change in LV dyssynchrony (r = 0.22 in the CRT-D group and r = 0.16 in the ICD-only group, all P < 0.001; Figure 4). Compared with the CRT-D group, few patients in the ICD-only group had a reduction in LV dyssynchrony. Changes in LV dyssynchrony and contractile function measured by GLS were significantly correlated with change in LV end-diastolic volume (r = 0.25 and 0.43, P < 0.001, respectively), change in LVESV (r = 0.25 and 0.41, P < 0.001, respectively), and change in LVEF (r = −0.29 and −0.42, P < 0.001, respectively) even after adjustment for treatment group (P < 0.001 for all). We observed a greater improvement in LV dyssynchrony and contractile function measured by GLS in the CRT-D group within all subgroups studied. However, significantly greater improvement in LV dyssynchrony was observed in patients with LBBB (interaction P = 0.001), non-ischaemic cardiomyopathy (interaction P = 0.003), and those with QRS width >150 ms (interaction P = 0.001) (Figure 5A). Similarly, a significantly greater improvement in LV contractile function measured by GLS was observed in patients with LBBB (interaction P-value < 0.001), non-ischaemic cardiomyopathy (interaction P-value = 0.002), and those with QRS width >150 ms (interaction P-value = 0.001) (Figure 5B).

Figure 3

Changes in left ventricular dyssynchrony and contractile function in implantable cardioverter defibrillator-only and cardiac resynchronization therapy-defibrillator groups. Data are presented as mean ± SD. Between-treatment-group differences in the change in left ventricular dyssynchrony and left ventricular contractile function measures from baseline to 12 months were assessed in analysis of covariance adjusting for treatment group, ischaemic aetiology, and baseline measure of dyssynchrony or strain.

Figure 3

Changes in left ventricular dyssynchrony and contractile function in implantable cardioverter defibrillator-only and cardiac resynchronization therapy-defibrillator groups. Data are presented as mean ± SD. Between-treatment-group differences in the change in left ventricular dyssynchrony and left ventricular contractile function measures from baseline to 12 months were assessed in analysis of covariance adjusting for treatment group, ischaemic aetiology, and baseline measure of dyssynchrony or strain.

Figure 4

Change in left ventricular contractile function measured by global longitudinal strain according to quartiles of change in dyssynchrony within-treatment group. Data are expressed as mean ± SEM. Note: the greater the absolute per cent reduction in left ventricular strain, the greater the improvement in left ventricular contractile function.

Figure 4

Change in left ventricular contractile function measured by global longitudinal strain according to quartiles of change in dyssynchrony within-treatment group. Data are expressed as mean ± SEM. Note: the greater the absolute per cent reduction in left ventricular strain, the greater the improvement in left ventricular contractile function.

Figure 5

(A) Effect of treatment on left ventricular dyssynchrony in subgroups. (B) Effect of treatment on left ventricular contractile function in subgroups.

Figure 5

(A) Effect of treatment on left ventricular dyssynchrony in subgroups. (B) Effect of treatment on left ventricular contractile function in subgroups.

Relationship between changes in dyssynchrony or contractile function and primary outcome

The primary outcome of death or HF event, whichever came first, occurred after the 1-year echocardiogram in 52 (15.9%) patients in the ICD-only group and in 30 (6.9%) patients in the CRT-D group, with a median post-year follow-up of 14.9 months (median total follow-up was 26.9 months). Improvement in LV dyssynchrony and LV contractile function measured by GLS at 1 year was associated with a subsequent reduction in the primary outcome of death or HF, adjusting for baseline dyssynchrony and contractile function, treatment arm, ischaemic status, and change in LVESV (Table 2). Each 20 ms decrease in LV dyssynchrony was associated with a 7% reduction in the primary outcome (P = 0.047); each one-point absolute improvement in LV contractile function measured by GLS over the 12-month period was associated with a 24% reduction in the primary outcome (P < 0.001). In a more fully adjusted model, only improvement in LV strain remained a significant predictor of the primary outcome of death or HF, even after adjustment for change in LVEF. Patients with worsening LV contractile function had the worst outcome whether dyssynchrony improved or worsened [adjusted hazard ratio (HR) of 2.99 (1.43–6.28), P = 0.004 and adjusted HR of 2.78 (1.34–5.77), P = 0.006, respectively] (Table 3).

Table 2

Relationship between changes in left ventricular dyssynchrony and contractile function measured by global longitudinal strain and primary outcome

 Unadjusted HR Adjusted HR for baseline, treatment, ischaemic status, ΔLVESV Multivariatea 
Improvement in dyssynchrony (per 20 ms decrease) 0.93 (0.89–0.98), P = 0.007 0.93 (0.87–0.99), P = 0.047 0.95 (0.89–1.02), P = 0.17 
Improvement in LV contractility (per 1% point improvement) 0.84 (0.78–0.91), P < 0.001 0.76 (0.66–0.85), P < 0.001 0.77 (0.68–0.86), P < 0.001 
 Unadjusted HR Adjusted HR for baseline, treatment, ischaemic status, ΔLVESV Multivariatea 
Improvement in dyssynchrony (per 20 ms decrease) 0.93 (0.89–0.98), P = 0.007 0.93 (0.87–0.99), P = 0.047 0.95 (0.89–1.02), P = 0.17 
Improvement in LV contractility (per 1% point improvement) 0.84 (0.78–0.91), P < 0.001 0.76 (0.66–0.85), P < 0.001 0.77 (0.68–0.86), P < 0.001 

Landmark analysis (n = 715). Eighty-two primary endpoints (52 in the ICD-only group and 30 in the CRT group); events rate per 100 patients-year were, respectively, 13.1 and 6.1 in the ICD-only vs. CRT-D group.

aAdjusted for baseline LV dyssynchrony or GLS, treatment, ischaemic status, ΔLVESV, ΔLVEF, age, gender, QRS, and LBBB.

Table 3

Hazard ratio for primary outcome after 1 year according change in left ventricular dyssynchrony and contractile function

 Better contractile function, less dyssynchrony (n = 212) Better contractile function, more dyssynchrony (n = 156) Worse contractile function, less dyssynchrony (n = 158) Worse contractile function, more dyssynchrony (n = 189) 
Unadjusted HR (95% CI) Reference 1.79 (0.81–3.94), P = 0.15 2.75 (1.34–5.63), P = 0.006 3.36 (1.70–6.64), P < 0.0001 
Adjusted HRa (95% CI) Reference 1.11 (0.48–2.56), P = 0.80 2.99 (1.43–6.28), P = 0.004 2.78 (1.34–5.77), P = 0.006 
 Better contractile function, less dyssynchrony (n = 212) Better contractile function, more dyssynchrony (n = 156) Worse contractile function, less dyssynchrony (n = 158) Worse contractile function, more dyssynchrony (n = 189) 
Unadjusted HR (95% CI) Reference 1.79 (0.81–3.94), P = 0.15 2.75 (1.34–5.63), P = 0.006 3.36 (1.70–6.64), P < 0.0001 
Adjusted HRa (95% CI) Reference 1.11 (0.48–2.56), P = 0.80 2.99 (1.43–6.28), P = 0.004 2.78 (1.34–5.77), P = 0.006 

aAdjusted for baseline strain or dyssynchrony, treatment, ischaemic status, ΔLVESV, age, gender, QRS, and LBBB.

Discussion

In the present analysis, we observed a significant improvement in both LV dyssynchrony and LV contractile function measured by GLS in the CRT-D group compared with the ICD-only group both in the total study population and within all subgroups studied. However, a significantly greater improvement in LV dyssynchrony and contractile function was observed in CRT-D patients with LBBB, non-ischaemic cardiomyopathy, and those with wider QRS. These changes were related to subsequent outcomes, suggesting that improvements in both synchrony and contractile function may account for a considerable portion of the benefit of CRT.

Several echocardiographic studies have shown that CRT acutely improves haemodynamic status then induces reduction in LV volumes, associated with an increase in LVEF and a structural reverse remodelling of the LV, as well as improvements in mitral regurgitation severity after long-term CRT.22–24 These benefits are now well established. However, whether these benefits are specifically due to improvements in synchrony or contractile function remains unknown. Although limited by the absence of outcomes data, prior smaller studies have shown significant improvement in LV dyssynchrony13,24–26 and contractile function27–29 after CRT. Our study confirms these earlier findings in a large multicentre study. Moreover, our results demonstrate a weak relationship between the changes in LV dyssynchrony and contractile function measured by GLS, suggesting that overall benefits may result from a more coordinated contraction of the LV with improved contractile efficiency. Although we can speculate that improvement in contractile function may be the result of improvement in synchrony, this remains only an association and our data cannot determine which is causal.

In our population, we observed substantial variation in the extent of LV resynchronization with CRT, although the vast majority of patients revealed some degree of reduction in LV dyssynchrony (72% of the patients in the CRT-D group). The presence of large areas of scar tissue throughout the LV,13,30 the presence of scar  in the area of the LV pacing lead,31 or a suboptimal lead position32,33 may explain the lack of LV resynchronization in some patients. Other factors such as gender34 and QRS morphology35 also identify patients who appear to derive more benefit of CRT.

Few studies have examined changes in multidirectional strain, a measure of contractile function, after CRT, and the relationship with LV reverse remodelling.27–29 In 141 patients with HF, Delgado et al. demonstrated that improvement in global LV strain after CRT was a long-term effect and was related to the extent of LV reverse remodelling. However, significant improvement in multidirectional strain and significant reverse remodelling was noted only in responders.27 In our population, ∼78% of the patients in the CRT-D group had improved contractile function to some extent, as measured by LV GLS. Improvements in the ICD-only group were likely due to optimized medical therapy, with 96% of the patients receiving angiotensin-converting enzyme-inhibitors or angiotensin receptor blocker, 93% receiving β-blockers, and 31% aldosterone antagonists.

Changes in LV dyssynchrony and contractile function measured by GLS were related to the extent of the LV reverse remodelling in both treatment groups, but to a greater extent in the CRT-D group. These results confirm, in a large population, the beneficial effects of CRT on LV mechanics and the relationship between these changes and outcome. Although these benefits of CRT are seen across subgroups, the greatest improvement in LV dyssynchrony and LV contractile function was observed in CRT-D patients with LBBB, non-ischaemic cardiomyopathy, and those with wider QRS, similar to the greater benefit observed in these subgroups in the overall MADIT-CRT population.4,35

The goal of the present analysis was to explore the pathophysiological mechanisms that lead to improved outcome in patients receiving CRT, but not to define a cut-off for LV dyssynchrony or to compare the various methods to assess dyssynchrony. We demonstrated that improvement in LV dyssynchrony and GLS at 1 year was predictive of a subsequent primary outcome of death or HF, adjusting for baseline, treatment group, and ischaemic status. Improvement in contractile function seems more closely related to clinical outcome than improvement in synchrony. In a fully adjusted model, only improvement in LV GLS remained a significant predictor of the primary outcome of death or HF, even after adjustment for change in LVEF. These assessments may have value in the evaluation of a CRT patient post-device implantation as a way to determine response early after implantation.

Our analysis is strengthened by the availability of detailed clinical characteristics and advanced echocardiographic measures in a large sample size, the availability of long-term clinical outcomes data, and the presence of a control group (ICD alone). We utilized a primary definition based on clinical response (survival free of event) rather than an arbitrary echocardiographic definition, as agreement between different methods to define response to cardiac resynchronization therapy has proven poor.36 Nevertheless, several limitations of this post hoc analysis should be noted. Although the investigators were blinded to the treatment assignment, the coronary sinus leads were occasionally visible in the apical view, an unavoidable problem in echocardiographic evaluation of CRT trials. As echocardiograms were obtained only at baseline and 12 months, we cannot determine how rapidly these changes in LV dyssynchrony and contractile function occurred. In addition, 201 patients underwent 12-month echocardiograms with devices turned off, in response to an early FDA request, and were not included in this analysis. We cannot assess the relationship between changes in LV synchrony and contractile function and outcomes in those patients who died or did not undergo the 12-month on-therapy echocardiogram. Only 761 patients (42% of the original cohort) had paired echocardiographic data available with devices turned on and adequate image quality for 2D speckle tracking. Still, this analysis represents the largest series of patients in a randomized controlled trial with these measures and outcome data available.

In summary, cardiac resynchronization therapy resulted in significantly greater improvement in both LV dyssynchrony and LV contractile function compared with ICD only, and changes in these measures were related to subsequent outcomes, suggesting that improvements in both synchrony and contractile function may account for a considerable portion of the benefit of CRT.

Funding

The MADIT-CRT trial was funded by Boston Scientific through a research grant to the University of Rochester, which in turn provided funding for core laboratories, including the echocardiography core laboratory.

Conflict of interest: S.D.S, E.F., W.J.H., W.Z., and A.J.M. have received research support for the conduct of the MADIT-CRT trial from Boston Scientific through a grant to the University of Rochester. S.D.S. and M.A.P. have served as consultants to Boston Scientific.

References

1
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
MIRACLE Study Group
Cardiac resynchronization in chronic heart failure
N Engl J Med
 , 
2002
, vol. 
346
 (pg. 
1845
-
1853
)
2
Cleland
JG
Daubert
JC
Erdmann
E
Freemantle
N
Gras
D
Kappenberger
L
Tavazzi
L
Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators
The effect of cardiac resynchronization on morbidity and mortality in heart failure
N Engl J Med
 , 
2005
, vol. 
352
 (pg. 
1539
-
1549
)
3
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
Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators
Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure
N Engl J Med
 , 
2004
, vol. 
350
 (pg. 
2140
-
2150
)
4
Moss
AJ
Hall
WJ
Cannom
DS
Klein
H
Brown
MW
Daubert
JP
Estes
NA
3rd
Foster
E
Greenberg
H
Higgins
SL
Pfeffer
MA
Solomon
SD
Wilber
D
Zareba
W
MADIT-CRT Trial Investigators
Cardiac-resynchronization therapy for the prevention of heart-failure events
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
1329
-
1338
)
5
Linde
C
Abraham
WT
Gold
MR
St John Sutton
M
Ghio
S
Daubert
C
REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group
Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms
J Am Coll Cardiol
 , 
2008
, vol. 
52
 (pg. 
1834
-
1843
)
6
Tang
AS
Wells
GA
Talajic
M
Arnold
MO
Sheldon
R
Connolly
S
Hohnloser
SH
Nichol
G
Birnie
DH
Sapp
JL
Yee
R
Healey
JS
Rouleau
JL
Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators
Cardiac resynchronization therapy for mild-to-moderate heart failure
N Engl J Med
 , 
2010
, vol. 
363
 (pg. 
2385
-
2395
)
7
Solomon
SD
Foster
E
Bourgoun
M
Shah
A
Viloria
E
Brown
MW
Hall
WJ
Pfeffer
MA
Moss
AJ
MADIT-CRT Investigators
Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome: multicenter automatic defibrillator implantation trial: cardiac resynchronization therapy
Circulation
 , 
2010
, vol. 
122
 (pg. 
985
-
992
)
8
Yu
CM
Bleeker
GB
Fung
JW
Schalij
MJ
Zhang
Q
van der Wall
EE
Chan
YS
Kong
SL
Bax
JJ
Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy
Circulation
 , 
2005
, vol. 
112
 (pg. 
1580
-
1586
)
9
Daubert
C
Gold
MR
Abraham
WT
Ghio
S
Hassager
C
Goode
G
Szili-Török
T
Linde
C
REVERSE Study Group
Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
1837
-
1846
)
10
Ypenburg
C
van Bommel
RJ
Borleffs
CJW
Bleeker
GB
Boersma
E
Schalij
MJ
Bax
JJ
 Long-term prognosis after cardiac resynchronization therapy is related to the extent of left ventricular reverse remodeling at midterm follow-up
 J Am Coll Cardiol
 , 
2009
, vol. 
53
 (pg. 
483
-
490
)
11
White
JA
Yee
R
Yuan
X
Krahn
A
Skanes
A
Parker
M
Klein
G
Drangova
M
Delayed enhancement magnetic resonance imaging predicts response to cardiac resynchronization therapy in patients with intraventricular dyssynchrony
J Am Coll Cardiol
 , 
2006
, vol. 
48
 (pg. 
1953
-
1960
)
12
Marsan
NA
Westenberg
JJ
Ypenburg
C
van Bommel
RJ
Roes
S
Delgado
V
Tops
LF
van der Geest
RJ
Boersma
E
de Roos
A
Schalij
MJ
Bax
JJ
Magnetic resonance imaging and response to cardiac resynchronization therapy: relative merits of left ventricular dyssynchrony and scar tissue
Eur Heart J
 , 
2009
, vol. 
30
 (pg. 
2360
-
2367
)
13
Delgado
V
Ypenburg
C
van Bommel
RJ
Tops
LF
Mollema
SA
Marsan
NA
Bleeker
GB
Schalij
MJ
Bax
JJ
Assessment of left ventricular dyssynchrony by speckle tracking strain imaging comparison between longitudinal, circumferential, and radial strain in cardiac resynchronization therapy
J Am Coll Cardiol
 , 
2008
, vol. 
51
 (pg. 
1944
-
1952
)
14
Amundsen
BH
Helle-Valle
T
Edvardsen
T
Torp
H
Crosby
J
Lyseggen
E
Støylen
A
Ihlen
H
Lima
JA
Smiseth
OA
Slørdahl
SA
Noninvasive myocardial strain measurement by speckle tracking echocardiography: validation against sonomicrometry and tagged magnetic resonance imaging
J Am Coll Cardiol
 , 
2006
, vol. 
47
 (pg. 
789
-
793
)
15
Mor-Avi
V
Lang
RM
Badano
LP
Belohlavek
M
Cardim
NM
Derumeaux
G
Galderisi
M
Marwick
T
Nagueh
SF
Sengupta
PP
Sicari
R
Smiseth
OA
Smulevitz
B
Takeuchi
M
Thomas
JD
Vannan
M
Voigt
JU
Zamorano
JL
Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography
J Am Soc Echocardiogr
 , 
2011
, vol. 
24
 (pg. 
277
-
313
)
16
Stanton
T
Leano
R
Marwick
TH
Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring
Circ Cardiovasc Imaging
 , 
2009
, vol. 
2
 (pg. 
356
-
364
)
17
Moss
AJ
Brown
MW
Cannom
DS
Daubert
JP
Estes
M
Foster
E
Greenberg
HM
Hall
WJ
Higgins
SL
Klein
H
Pfeffer
M
Wilber
D
Zareba
W
Multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT): design and clinical protocol
Ann Noninvasive Electrocardiol
 , 
2005
, vol. 
10
 
Suppl. 4
(pg. 
34
-
43
)
18
Yu
CM
Fung
JW
Zhang
Q
Chan
CK
Chan
YS
Lin
H
Kum
LC
Kong
SL
Zhang
Y
Sanderson
JE
Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy
Circulation
 , 
2004
, vol. 
110
 (pg. 
66
-
73
)
19
Shin
SH
Hung
CL
Uno
H
Hassanein
AH
Verma
A
Bourgoun
M
Køber
L
Ghali
JK
Velazquez
EJ
Califf
RM
Pfeffer
MA
Solomon
SD
Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators
Mechanical dyssynchrony after myocardial infarction in patients with left ventricular dysfunction, heart failure, or both
Circulation
 , 
2010
, vol. 
121
 (pg. 
1096
-
1103
)
20
Tanaka
H
Nesser
HJ
Buck
T
Oyenuga
O
Jánosi
RA
Winter
S
Saba
S
Gorcsan
J
3rd
Dyssynchrony by speckle-tracking echocardiography and response to cardiac resynchronization therapy: results of the Speckle Tracking and Resynchronization (STAR) study
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
1690
-
1700
)
21
Cho
GY
Marwick
TH
Kim
HS
Kim
MK
Hong
KS
Oh
DJ
Global 2-dimensional strain as a new prognosticator in patients with heart failure
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
618
-
624
)
22
Leclercq
C
Cazeau
S
Le Breton
H
Ritter
P
Mabo
P
Gras
D
Pavin
D
Lazarus
A
Daubert
JC
Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure
J Am Coll Cardiol
 , 
1998
, vol. 
32
 (pg. 
1825
-
1831
)
23
Kass
DA
Chen
CH
Curry
C
Talbot
M
Berger
R
Fetics
B
Nevo
E
Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay
Circulation
 , 
1999
, vol. 
99
 (pg. 
1567
-
1573
)
24
Bleeker
GB
Mollema
SA
Holman
ER
Van de Veire
N
Ypenburg
C
Boersma
E
van der Wall
EE
Schalij
MJ
Bax
JJ
Left ventricular resynchronization is mandatory for response to cardiac resynchronization therapy: analysis in patients with echocardiographic evidence of left ventricular dyssynchrony at baseline
Circulation
 , 
2007
, vol. 
116
 (pg. 
1440
-
1448
)
25
Yu
CM
Chau
E
Sanderson
JE
Fan
K
Tang
MO
Fung
WH
Lin
H
Kong
SL
Lam
YM
Hill
MR
Lau
CP
Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure
Circulation
 , 
2002
, vol. 
105
 (pg. 
438
-
445
)
26
Bax
JJ
Bleeker
GB
Marwick
TH
Molhoek
SG
Boersma
E
Steendijk
P
van der Wall
EE
Schalij
MJ
Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy
J Am Coll Cardiol
 , 
2004
, vol. 
44
 (pg. 
1834
-
1840
)
27
Delgado
V
Ypenburg
C
Zhang
Q
Mollema
SA
Fung
JW
Schalij
MJ
Yu
CM
Bax
JJ
Changes in global left ventricular function by multidirectional strain assessment in heart failure patients undergoing cardiac resynchronization therapy
J Am Soc Echocardiography
 , 
2009
, vol. 
22
 (pg. 
688
-
694
)
28
Reant
P
Zaroui
A
Donal
E
Mignot
A
Bordachar
P
Deplagne
A
Solnon
A
Ritter
P
Daubert
JC
Clementy
J
Leclercq
C
Roudaut
R
Habib
G
Lafitte
S
Identification and characterization of super-responders after cardiac resynchronization therapy
Am J Cardiol
 , 
2010
, vol. 
105
 (pg. 
1327
-
1335
)
29
Zhang
Q
Fung
JW
Yip
GW
Chan
JY
Lee
AP
Lam
YY
Wu
LW
Wu
EB
Yu
CM
Improvement of left ventricular myocardial short-axis, but not long-axis function or torsion after cardiac resynchronisation therapy: an assessment by two-dimensional speckle tracking
Heart
 , 
2008
, vol. 
94
 (pg. 
1464
-
1671
)
30
D'Andrea
A
Caso
P
Scarafile
R
Riegler
L
Salerno
G
Castaldo
F
Gravino
R
Cocchia
R
Del Viscovo
L
Limongelli
G
Di Salvo
G
Ascione
L
Iengo
R
Cuomo
S
Santangelo
L
Calabrò
R
Effects of global longitudinal strain and total scar burden on response to cardiac resynchronization therapy in patients with ischaemic dilated cardiomyopathy
Eur J Heart Fail
 , 
2009
, vol. 
11
 (pg. 
58
-
67
)
31
Becker
M
Zwicker
C
Kaminski
M
Napp
A
Altiok
E
Ocklenburg
C
Friedman
Z
Adam
D
Schauerte
P
Marx
N
Hoffmann
R
Dependency of cardiac resynchronization therapy on myocardial viability at the LV lead position
JACC Cardiovasc Imaging
 , 
2011
, vol. 
4
 (pg. 
366
-
374
)
32
Suffoletto
MS
Dohi
K
Cannesson
M
Saba
S
Gorcsan
J
3rd
Novel speckle-tracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy
Circulation
 , 
2006
, vol. 
113
 (pg. 
960
-
968
)
33
Singh
JP
Klein
HU
Huang
DT
Reek
S
Kuniss
M
Quesada
A
Barsheshet
A
Cannom
D
Goldenberg
I
McNitt
S
Daubert
JP
Zareba
W
Moss
AJ
Left ventricular lead position and clinical outcome in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) Trial
Circulation
 , 
2011
, vol. 
123
 (pg. 
1159
-
1166
)
34
Arshad
A
Moss
AJ
Foster
E
Padeletti
L
Barsheshet
A
Goldenberg
I
Greenberg
H
Hall
WJ
McNitt
S
Zareba
W
Solomon
S
Steinberg
JS
MADIT-CRT Executive Committee
Cardiac resynchronization therapy is more effective in women than in men: the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) trial
J Am Coll Cardiol
 , 
2011
, vol. 
57
 (pg. 
813
-
820
)
35
Zareba
W
Klein
H
Cygankiewicz
I
Hall
WJ
McNitt
S
Brown
M
Cannom
D
Daubert
JP
Eldar
M
Gold
MR
Goldberger
JJ
Goldenberg
I
Lichstein
E
Pitschner
H
Rashtian
M
Solomon
S
Viskin
S
Wang
P
Moss
AJ
on behalf of the MADIT-CRT Investigators
Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT)
Circulation
 , 
2011
, vol. 
123
 (pg. 
1061
-
1072
)
36
Fornwalt
BK
Sprague
WW
BeDell
P
Suever
JD
Gerritse
B
Merlino
JD
Fyfe
DA
León
AR
Oshinski
JN
Agreement is poor among current criteria used to define response to cardiac resynchronization therapy
Circulation
 , 
2010
, vol. 
121
 (pg. 
1985
-
1991
)

Author notes

These authors contributed equally to this work.

Supplementary data

Comments

0 Comments