CLINICAL PERSPECTIVE

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(Circulation. 2007;116:1440-1448.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Left Ventricular Resynchronization Is Mandatory for Response to Cardiac Resynchronization Therapy

Analysis in Patients With Echocardiographic Evidence of Left Ventricular Dyssynchrony at Baseline

Gabe B. Bleeker, MD, PhD; Sjoerd A. Mollema, MD; Eduard R. Holman, MD, PhD; Nico Van De Veire, MD; Claudia Ypenburg, MD; Eric Boersma, PhD; Ernst E. van der Wall, MD, PhD; Martin J. Schalij, MD, PhD; Jeroen J. Bax, MD, PhD

From the Department of Cardiology, Leiden University Medical Center, Leiden (G.B.B., S.A.M., E.R.H., N.V.D.V., C.Y., E.E.v.d.W., M.J.S., J.J.B.); Interuniversity Cardiology Institute Netherlands, Utrecht (G.B.B.); and Department of Epidemiology and Statistics, Erasmus University, Erasmus (E.B.), the Netherlands.

Correspondence to Gabe B. Bleeker, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail g.b.bleeker{at}lumc.nl

Received November 17, 2006; accepted July 16, 2007.

	Abstract

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Background— Recent studies have demonstrated that a positive response to cardiac resynchronization therapy (CRT) is related to the presence of preimplantation left ventricular (LV) dyssynchrony. The time course and the extent of LV resynchronization after CRT implantation and their relationship to response are currently unknown.

Methods and Results— One hundred consecutive patients scheduled for implantation of a CRT device were prospectively included if they met the following criteria: New York Heart Association class III to IV, LV ejection fraction 35%, QRS duration >120 ms, and LV dyssynchrony (65 ms) on color-coded tissue Doppler imaging. Immediately after CRT implantation, LV dyssynchrony was reduced from 114±36 to 40±33 ms (P<0.001), which persisted at the 6-month follow-up (35±31 ms; P<0.001 versus baseline; P=0.14 versus immediately after implantation). At the 6-month follow-up, 85% of patients were classified as responders to CRT (defined as >10% reduction in LV end-systolic volume). Immediately after implantation, the responders to CRT demonstrated a significant reduction in LV dyssynchrony from 115±37 to 32±23 ms (P<0.001). The nonresponders, however, did not show a significant reduction in LV dyssynchrony (106±29 versus 79±44 ms; P=0.08). If the extent of acute LV resynchronization was <20%, response to CRT at the 6-month follow-up was never observed. Conversely, 93% of patients with LV resynchronization 20% responded to CRT.

Conclusions— LV resynchronization after CRT is an acute phenomenon and predicts response to CRT at 6-month follow-up in patients with echocardiographic evidence of LV dyssynchrony at baseline.

Key Words: cardiac resynchronization therapy • dyssynchrony • imaging • resynchronization

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Cardiac resynchronization therapy (CRT) is considered an important breakthrough in the treatment of selected patients with drug-refractory heart failure. Recent large randomized trials have clearly demonstrated the beneficial effects of CRT on heart failure symptoms and left ventricular (LV) systolic function. In addition, CRT resulted in a reduction in heart failure hospitalizations and an improvement in survival.^1–4 Despite these impressive results, a relatively high percentage of patients failed to respond to CRT.^1,5–7 Approximately 30% of patients failed to show improvement in clinical symptoms, and 40% to 50% of patients had no improvement in LV function on echocardiography.^1,5–7 Detailed analysis revealed that none of the established CRT selection criteria (New York Heart Association [NYHA] class III to IV, LV ejection fraction 35%, and QRS duration >120 ms) were able to predict a positive response to CRT.^5,7 Recent studies have indicated that the benefit from CRT is related to the presence of LV dyssynchrony before implantation.^5–10 Indeed, patient selection based on echocardiographic detection of LV dyssynchrony resulted in a superior response rate compared with patient selection based on QRS duration alone.^5–10 However, the presence of preimplantation LV dyssynchrony may not be the only determinant of response to CRT because some patients with preimplantation LV dyssynchrony still do not respond to CRT. It is currently unclear whether a reduction in LV dyssynchrony (LV resynchronization) after implantation of the CRT device is mandatory for a positive response. Accordingly, a prospective analysis in patients with preimplantation LV dyssynchrony on color-coded tissue Doppler imaging (TDI) was performed to answer the following questions: (1) What is the time course of LV resynchronization after CRT; does LV resynchronization occur quickly or develop gradually over time? (2) What extent of LV resynchronization is obtained after CRT? (3) Is LV resynchronization necessary for response to CRT, and if so, which extent of LV resynchronization is the best predictor of response to CRT?

Editorial p 1434

Clinical Perspective p 1448

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population and Protocol
Consecutive heart failure patients scheduled for implantation of a CRT device were included in this study. The selection criteria for CRT included moderate to severe heart failure (NYHA class III or IV), LV ejection fraction 35%, and QRS duration >120 ms. In addition, patients had to show substantial LV dyssynchrony (65 ms) on TDI. Patients with a recent myocardial infarction (<3 months), decompensated heart failure, or unsuccessful LV lead implantation were excluded. Before CRT implantation, clinical status was assessed, and 2-dimensional echocardiography was performed to determine LV volumes and LV ejection fraction. Assessment of LV dyssynchrony with TDI was repeated immediately after CRT implantation and at a 6-month follow-up. The clinical status and changes in LV ejection fraction and LV volumes were reassessed at the 6-month follow-up.

Clinical Evaluation
Evaluation of clinical status included assessment of NYHA functional class, quality-of-life score (using the Minnesota Living With Heart Failure Questionnaire), and evaluation of exercise capacity with the 6-minute hall-walk test. All parameters were reassessed at the 6-month follow-up.

Echocardiography
Patients were imaged in the left lateral decubitus position with a commercially available system (Vingmed System Seven, General Electric-Vingmed, Milwaukee, Wis). Images were obtained with a 3.5-MHz transducer at a depth of 16 cm in the parasternal and apical views (standard long-axis, 2- and 4-chamber images). Standard 2-dimensional and color Doppler data triggered to the QRS complex were saved in cine-loop format. The LV volumes (end systolic, end diastolic) and LV ejection fraction were calculated from the conventional apical 2- and 4-chamber images using the biplane Simpson technique.¹¹

Patients with a reduction of >10% in LV end-systolic volume at the 6-month follow-up were considered responders to CRT.¹² In addition, patients who died of progressive heart failure before the 6-month follow-up assessment were classified as nonresponders.

The severity of mitral regurgitation was graded semiquantitatively from color-flow Doppler in the conventional parasternal long-axis and apical 4-chamber images. Mitral regurgitation was characterized as follows: mild=1+ (jet area/left atrial area <10%), moderate=2+ (jet area/left atrial area 10% to 20%), moderately severe=3+ (jet area/left atrial area 20% to 45%), and severe=4+ (jet area/left atrial area >45%).¹³ All echocardiographic measurements after CRT implantation were made with the device in active pacing mode.

LV Dyssynchrony Assessment With Color-Coded TDI
In addition to the conventional echocardiographic examination, TDI was performed to assess LV dyssynchrony. For TDI, color Doppler frame rates were >80 frames per second; pulse repetition frequencies were between 500 Hz and 1 KHz, resulting in aliasing velocities between 16 and 32 cm/s. TDI parameters were measured from color-coded images of 3 consecutive heartbeats by offline analysis. To determine LV dyssynchrony, the sample volume (6x6 mm) was placed in the LV basal parts of the anterior, inferior, septal, and lateral walls (using the 2-and 4-chamber apical views), and the time interval between the onset of the QRS complex and the peak systolic velocity per region was derived (ie, the electrosystolic delays). The analysis of peak systolic velocities was limited to the LV ejection period; postsystolic peaks were excluded. To mark the LV ejection period, the opening and closure of the aortic valve were measured from the pulsed-wave Doppler signals in the LV outflow tract and subsequently superimposed on the TDI curves (using the "event-timing" function on the Echopac echo analysis software, General Electric-Vingmed). To ensure highly interpretable and reproducible TDI curves (and to minimize artifacts), high frame rates are crucial. The highest possible frame rates were achieved by narrowing the 2- and 4-chamber apical TDI views down to the left ventricle (ie, excluding the right ventricle and atria). LV dyssynchrony was defined as the maximum delay between peak systolic velocities among the 4 walls within the left ventricle (most frequently observed between the interventricular septum and the lateral wall). On the basis of previous data, a cutoff value of 65 ms was used as a marker of LV dyssynchrony.⁷ Previously reported interobserver agreement and intraobserver agreement for assessment of LV dyssynchrony were 90% and 96%, respectively.¹⁴ The percentage of immediate LV resynchronization was defined as the difference (%) between preimplantation LV dyssynchrony and LV dyssynchrony immediately after CRT implantation.

Data were analyzed with commercial software (Echopac version 5.0.1). Echocardiographic data were analyzed by 2 independent observers who were blinded to all other patient data.

Pacemaker Implantation
The LV pacing lead was inserted transvenously via the subclavian route. A coronary sinus venogram was obtained with a balloon catheter. Next, the LV pacing lead was inserted through the coronary sinus with the help of an 8F guiding catheter and positioned as far as possible in the venous system, preferably in a (postero) lateral vein. The right atrial and right ventricular leads were positioned conventionally. CRT device and lead implantation was successful in all patients without major complications (Contak TR or Contak Renewal TR2/1/2/4, Guidant, and Insync [Marquis] III or Sentry, Medtronic Inc, Minneapolis, Minn). Two types of LV leads were used (Easytrak, Guidant, or Attain, Medtronic Inc). After implantation, the LV lead position was assessed from the frontal and lateral chest x-rays. CRT devices were programmed in the DDD(R) mode in patients in normal sinus rhythm and in the VVIR mode in patients in atrial fibrillation. No adjustments were made to the V-V interval before the 6-month follow-up assessment.

Statistical Analysis
Continuous data were expressed as mean±SD and compared through the use of the 2-tailed Student t test for paired and unpaired data when appropriate. Categorical variables were compared by use of the ² test with Yates’ correction. Linear regression analysis was performed to determine the relationship between immediate LV resynchronization and LV reverse remodeling at the 6-month follow-up. Univariable and multivariable linear regression and logistic regression analyses were performed to study the relationship between baseline and immediate post-CRT implantation variables and response to CRT at the 6-month follow-up. For all tests, a value of P<0.05 was considered statistically significant.

All authors had full access to and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

	Results

Top Abstract Introduction Methods Results Discussion References

 
A total of 100 consecutive patients were prospectively included. The study population consisted of 86 men and 14 women with a mean age of 67±11 years. By definition, all patients had preimplantation LV dyssynchrony 65 ms (mean, 114±36 ms). The baseline characteristics of the patients are summarized in Table 1.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics

Immediately after CRT implantation, QRS duration was reduced from 168±27 to 151±25 ms (P<0.001). One patient died at 3 months after CRT implantation as a result of worsening heart failure. Accordingly, this patient did not have the follow-up assessment at 6 months and was classified as a nonresponder to CRT. In the remaining patients, a significant improvement in NYHA class was observed (from 3.0±0.2 to 2.0±0.5; P<0.001) at the 6-month follow-up. In addition, the quality-of-life score decreased from 38±16 to 19±15 (P<0.001), and the 6-minute walking distance increased from 292±108 to 407±100 m (P<0.001). Echocardiography at 6-month follow-up revealed a significant improvement in LV ejection fraction from 23±7% to 33±10% (P<0.001) and significant LV reverse remodeling, with a decrease in LV end-diastolic volume from 243±76 to 204±73 mL (P<0.001) and a decrease in LV end-systolic volume from 188±71 to 136±63 mL (P<0.001).

Eighty-five patients (85%) showed a reduction of >10% in LV end-systolic volume at the 6-month follow-up and were therefore classified as responders to CRT.

LV Resynchronization After CRT
Immediately after CRT implantation, TDI demonstrated a reduction in LV dyssynchrony from 114±36 to 40±33 ms (P<0.001). At the 6-month follow-up, the reduction in LV dyssynchrony by CRT was sustained with an LV dyssynchrony of 35±31 ms (P<0.001 versus baseline, P=0.14 versus immediately after implantation) (Figure 1).

View larger version (10K): [in this window] [in a new window]   Figure 1. Time course of LV resynchronization after CRT implantation in all patients (n=100).

Although the reduction in LV dyssynchrony after CRT was highly significant, with an immediate reduction in LV dyssynchrony of 65% and a 69% reduction at the 6-month follow-up, not all patients experienced a similar extent of LV resynchronization. The distribution of the extent of immediate LV resynchronization after CRT is displayed in Figure 2. In most patients, CRT induced a 60% reduction in LV dyssynchrony both immediately after implantation (n=61, 61%) and at the 6-month follow-up (n=67, 67%). In other patients, however, CRT resulted in only a minimal reduction or even an increase in LV dyssynchrony, although this occurred in <10% of all patients (Figure 2). The percentage of acute LV resynchronization was not different between the patients with sinus rhythm or atrial fibrillation (66±30% versus 63±30%; P=0.74) or between patients with ischemic or nonischemic cardiomyopathy (62±29% versus 68±30%; P=0.46).

View larger version (10K): [in this window] [in a new window]   Figure 2. Extent of the decrease in LV dyssynchrony immediately after CRT implantation.

LV Resynchronization Versus Response to CRT
As indicated above, 85 patients (85%) showed a reduction of >10% in LV end-systolic volume at the 6-month follow-up and were therefore classified as responders to CRT. Fourteen patients (14%) had a reduction 10% in LV end-systolic volume, and 1 patient died of progressive heart failure before the 6-month follow-up; these patients were classified as nonresponders to CRT (15%).

At baseline, no significant differences were observed between responders and nonresponders (Table 2). In particular, baseline LV dyssynchrony was similar between responders and nonresponders (115±37 versus 106±29 ms; P=0.49). The prevalence of ischemic cardiomyopathy was higher in the nonresponders, although this difference was not statistically significant (80% versus 55%; P=0.13). There was a trend toward a lower percentage of reduction in LV end-systolic volume at the 6-month follow-up between patients with ischemic versus nonischemic cardiomyopathy (24±21% versus 30±18% reduction in LV end-systolic volume, respectively; P=0.13).

View this table: [in this window] [in a new window]   TABLE 2. Patients With LV Reverse Remodeling at the 6-Month Follow-Up (Defined as a Reduction in LV End-Systolic Volume >10%; n=85) Versus Patients Without LV Reverse Remodeling (Reduction in LV End-Systolic Volume 10%): Clinical and Echocardiographic Variables at Baseline and the 6-Month Follow-Up

By definition, LV end-systolic volume did not decrease in the nonresponders at the 6-month follow-up (170±79 mL at baseline versus 177±73 mL at follow-up; P=0.19). In contrast, the responders showed a significant reduction in LV end-systolic volume from 190±69 to 130±59 mL (P<0.001). In addition, the nonresponders showed no improvement in LV ejection fraction (from 24±7% to 25±7%; P=0.64), whereas the responders improved from 23±7% to 34±9% (P<0.001) (Table 2).

An interesting observation was the difference in immediate LV resynchronization between the responders and nonresponders. The patients without response showed no significant reduction in LV dyssynchrony (from 106±29 to 79±44 ms; P=0.08), whereas the responders demonstrated a significant reduction in LV dyssynchrony from 115±37 to 32±23 ms (P<0.001) (Figure 3).

View larger version (10K): [in this window] [in a new window]   Figure 3. Immediate decrease in LV dyssynchrony in the patients with response to CRT (n=85 [85%], defined as >10% reduction in LV end-systolic volume) vs patients without response (n=15 [15%]).

In the multivariable regression analysis, 3 variables were related to the absolute change in LV end-systolic volume at the 6-month follow-up (r=0.59, P<0.001): the extent of immediate LV resynchronization (P<0.001), baseline LV end-diastolic volume (P<0.001), and baseline severity of mitral regurgitation (P=0.02). In the multivariable logistic analysis including all studied variables (including patient age, gender, cause of heart failure, QRS duration, NYHA class, quality-of-life score, 6-minute walking distance, LV ejection fraction, LV end-systolic volume, LV end-diastolic volume, mitral regurgitation, LV dyssynchrony, and presence or absence of acute LV resynchronization), immediate LV resynchronization was the only variable that was predictive of response to CRT at the 6-month follow-up.

Linear regression analysis demonstrated a significant relationship between the immediate reduction in LV dyssynchrony and the reduction in LV end-systolic volume at the 6-month follow-up (y=0.29x+8; r=0.41; n=99; P<0.001) (Figure 4).

View larger version (12K): [in this window] [in a new window]   Figure 4. Relationship between immediate LV resynchronization and reduction in LV end-systolic volume at the 6-month follow-up (y=0.29x+8; n=99; r=0.41; P<0.001).

Of interest, when patients showed <20% LV resynchronization (n=9) immediately after CRT, response to CRT never occurred. In the patient who died of progressive heart failure before the 6-month follow-up assessment, LV dyssynchrony showed an immediate increase from 140 to 160 ms. Conversely, 85 of 91 patients with 20% LV resynchronization immediately after CRT implantation responded to CRT at the 6-month follow-up. Applying this cutoff value of 20% immediate LV resynchronization resulted in positive and negative predictive values of 100% and 93%, respectively, for the prediction of response to CRT at the 6-month follow-up, with an area under the curve of 0.84. Importantly, no differences were observed between the characteristics of the patients with and without immediate LV resynchronization, except that in patients without LV resynchronization, the LV lead was located more frequently in the anterior LV segments (2% versus 33%; P<0.01; Table 3). An interesting observation was that all patients without LV resynchronization and a posterior or lateral LV lead position had ischemic cardiomyopathy (n=6), whereas in the 3 patients with nonischemic cardiomyopathy, the LV lead was located in the anterior LV segments. Of the 9 patients without an immediate decrease in LV dyssynchrony (defined as an acute decrease of <20% in LV dyssynchrony), 5 patients showed an acute increase in LV dyssynchrony (from 108±31 to 124±29 ms; P<0.05). The LV lead position was in the anterior LV segments in 2 patients, in the lateral segments in 2 patients, and in the posterior LV region in 1 patient. Immediately after CRT implantation, the patients without acute LV resynchronization did not demonstrate a reduction in QRS duration (from 157±17 to 152±27 ms; P=0.69), whereas the patients with acute LV resynchronization had a significant reduction in QRS duration (from 169±28 to 151±24 ms; P<0.001).

View this table: [in this window] [in a new window]   TABLE 3. Baseline Characteristics in Patients With LV Resynchronization (20% Reduction in LV Dyssynchrony; n=91) Versus Patients Without LV Resynchronization (n=9)

At the 6-month follow-up, the patients with immediate LV resynchronization had a significant reduction in mitral regurgitation from grade 1.6±1.0 to 1.1±0.8 (P<0.001), whereas patients without acute LV resynchronization after CRT did not experience a reduction in mitral regurgitation grade at the 6-month follow-up (from 1.8±1.3 to 1.9±1.0; P=0.83).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The main findings of the present study can be summarized as follows. First, LV resynchronization after CRT occurs acutely and is sustained at 6 months but without further resynchronization over time. Large interindividual variation in the extent of LV resynchronization was observed, but the vast majority revealed >60% reduction in LV dyssynchrony immediately after CRT implantation. Finally, <20% resynchronization never resulted in response to CRT, whereas 93% of patients with 20% resynchronization responded to CRT at the 6-month follow-up.

Mechanism of Response to CRT
Recent studies have clearly demonstrated that the presence of substantial LV dyssynchrony before implantation is an important predictor of a response to CRT,^5–9 which may be superior over the traditional selection criteria (severe heart failure, depressed LV function, and wide QRS complex). For example, Dohi et al¹⁵ demonstrated that the extent of LV dyssynchrony was the only preimplantation parameter that was different between responders and nonresponders to CRT; responders had significantly larger septal to posterior peak wall strain than did nonresponders (249±94 versus 137±136 ms; P<0.05).

In the present study, all patients had echocardiographic evidence of LV dyssynchrony, and the echocardiographic response rate (defined as a decrease of >10% in LV end-systolic volume at the 6-month follow-up) was indeed much higher (85%) than in previous studies that included patients selected according to the traditional CRT selection criteria; these studies reported echocardiographic response rates in the range of 50% to 55%.^5,6,16 The present findings strongly support the use of echocardiographic selection of potential candidates for CRT.

The parameter for LV dyssynchrony used in the present study was derived previously from 85 heart failure patients undergoing CRT who were evaluated with color-coded TDI.⁷ Receiver-operating characteristics curve analysis revealed that LV dyssynchrony 65 ms (as determined from 4 basal LV segments) yielded a sensitivity and specificity of 92% to predict LV reverse remodeling after CRT implantation.⁷ On the basis of this predefined cutoff value, only patients with evidence of LV dyssynchrony 65 ms on TDI were included in the present study.

The definition of response used in the present study (reduction >10% in LV end-systolic volume at the 6-month follow-up) was derived from a study by Yu et al,¹² who studied 141 patients undergoing CRT and observed that a reduction in LV end-systolic volume after 3 to 6 months of CRT was the most important predictor of all-cause and cardiovascular death, whereas clinical parameters were unable to predict response to CRT. Receiver-operating characteristics curve analysis revealed that a cutoff value of 10% reduction in LV end-systolic volume was the optimal cutoff value for prediction of improved survival after CRT.

Time Course and Extent of LV Resynchronization After CRT
Various studies have reported on LV resynchronization after CRT.^6,7,17,18 Most studies showed immediate resynchronization after CRT. For example, Breithardt et al⁹ studied the acute effects of CRT on the extent of LV dyssynchrony in 34 patients by using echocardiographic phase analysis. Immediately after implantation, a 37% decrease in LV dyssynchrony was observed (from 104°±41° to 66°±42°; P<0.001).

However, the time course of LV resynchronization during follow-up is currently unknown, and the question of whether initial LV resynchronization is followed by a further reduction in LV dyssynchrony is unanswered. The present findings clearly demonstrate that LV resynchronization is an acute phenomenon that occurs immediately after CRT implantation. At a mid-term follow-up, the extent of immediate LV resynchronization is sustained, but a further reduction in LV dyssynchrony could not be demonstrated (Figure 1). An interesting observation is the high interindividual variation in the extent of immediate LV resynchronization after CRT implantation. Although most patients demonstrated 60% reduction in LV dyssynchrony, some patients demonstrated only a minimal amount of LV resynchronization or even experienced an increase in LV dyssynchrony.

Lack of LV Resynchronization
In search for optimal prediction of response to CRT, previous studies have shown that patients with LV dyssynchrony have a relatively high likelihood of responding to CRT, whereas patients without LV dyssynchrony do not respond, although not all patients with LV dyssynchrony responded to CRT.^7,15–17 In the present study, patients were selected on the basis of the presence of LV dyssynchrony before CRT implantation, resulting in a high response rate (85%), but 15% of patients still did not respond. Comparison of responders and nonresponders revealed no differences in baseline clinical and echocardiographic characteristics (Table 2). Interestingly, further analysis of the individual patient data revealed that the extent of immediate LV resynchronization can be used to optimize the prediction of response. Patients with <20% reduction in LV dyssynchrony never responded to CRT. In contrast, patients with LV resynchronization 20% had an excellent response rate of 93%.

Although the number of patients without LV resynchronization in the present study is low (n=9), a suboptimal position of the LV pacing lead appears to be related to the lack of LV resynchronization. Rossillo et al¹⁹ recently demonstrated in 233 consecutive patients that placement of the LV pacing lead in the lateral or posterolateral branches of the coronary sinus was associated with a superior improvement in LV function (LV ejection fraction from 19% to 27%; P<0.05) compared with patients with an anterior LV pacing lead location (LV ejection fraction from 18% to 20%; P=NS).

Recent data have indicated that in heart failure patients the posterolateral LV segments are usually the latest activated LV segments.²⁰ Pacing the left ventricle outside the area of latest activation resulted in less improvement in LV ejection fraction and LV volumes than did pacing in the area of latest activation. Murphy et al²¹ demonstrated that pacing the LV in a remote area (eg, the anterior LV segments) even resulted in a worsening of LV volumes, with a 9% increase in LV end-systolic volume during follow-up. The present study demonstrated that minimal or absent LV resynchronization may be a potential mechanism for the lack of benefit from CRT in patients with suboptimal LV lead positioning.

A second potential explanation for a lack of LV resynchronization may be the presence of large areas of scar tissue throughout the left ventricle (total scar burden) or the presence of scar tissue in the area of the LV pacing lead. Bleeker et al²² recently demonstrated in 40 patients that CRT is unable to reduce LV dyssynchrony (from 84±46 to 78±41 ms; P=NS) in the presence of scar tissue in the posterolateral LV segments. As a result, the (clinical) response rate to CRT in patients with posterolateral scar tissue was poor (11%), whereas patients with severe baseline LV dyssynchrony without posterolateral scar tissue had an excellent (clinical) response rate of 95%.²² In addition, several studies have recently demonstrated that the amount of LV scar tissue is highly predictive for response to CRT regardless of baseline LV dyssynchrony.^23,24 The presence of scar tissue most likely prevents a normal activation of the myocardium because the activation front is delayed or stopped by large areas of scar tissue, resulting in lack of LV resynchronization. A potential beneficial treatment strategy in patients without initial LV resynchronization is V-V delay optimization.^25,26 Previous studies have shown that optimization of the V-V pacing delay may result in a (further) reduction in LV dyssynchrony and may therefore be beneficial in patients without initial LV resynchronization.²⁶ Interestingly, Leon et al²⁶ demonstrated that patients with a history of myocardial infarction more frequently benefit from LV preexcitation during V-V optimization, which may be the additional activation delay caused by large amounts of scar tissue. In the present study, V-V optimization was not performed before the 6-month follow-up assessment, which may be considered a limitation.

In addition, whether repositioning of the LV lead to the area of latest activation or to an area without myocardial scar tissue will result in LV resynchronization in patients without an initial reduction in LV dyssynchrony needs further study.

Study Limitations
Although none of the patients with acute LV resynchronization <20% responded to CRT (in contrast to a response rate of 93% in patients with acute LV resynchronization 20%), the cutoff value of a 20% acute reduction in LV dyssynchrony needs further validation.

In recent years, a wide variety of echocardiographic techniques, ranging from simple M-mode echocardiography to more advanced techniques such as TDI and strain imaging, have been introduced for quantification of LV dyssynchrony. All techniques have been evaluated only in small, single-center studies, indicating the clear need for larger multicenter studies directly comparing the different techniques. In addition, the cutoff value of 65 ms for LV dyssynchrony measurement was validated in a single study. Further studies are required to confirm 65 ms as the optimal cutoff value for LV dyssynchrony assessment. Furthermore, the differentiation between passive myocardial motion and active contraction of LV segments is possible with strain or strain rate imaging but not with TDI. Still, TDI is among the most widely studied techniques for LV dyssynchrony assessment, with a high predictive value for response to CRT.¹⁰ The fact that the present study included only patients with echocardiographic evidence of LV dyssynchrony limits the generalizability of the study because the effects of CRT on LV dyssynchrony in patients without preimplantation LV dyssynchrony were not studied. The power to detect changes in the group without immediate response to CRT was limited by the small number of patients in this group.

Conclusions
In the present study, LV resynchronization after CRT is an acute phenomenon without further reduction in LV dyssynchrony during follow-up. Despite the presence of substantial LV dyssynchrony before implantation, patients with a <20% immediate reduction in LV dyssynchrony never showed response to CRT at the 6-month follow-up, which indicates that resynchronization is mandatory for response to CRT.

	Acknowledgments

 
Source of Funding

Dr Bleeker is supported by Dutch Heart Foundation grant 2002B109.

Disclosures

None.

	References

Top Abstract Introduction Methods Results Discussion References

 

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CLINICAL PERSPECTIVE

Despite the impressive results of cardiac resynchronization therapy (CRT) in large randomized trials (including >4000 patients), 30% to 40% of patients who meet established patient selection criteria (New York Heart Association class III to IV, left ventricular [LV] ejection fraction 35%, and QRS duration >120 ms) fail to respond. Recent studies have found that the benefit from CRT is related to the presence of LV dyssynchrony before implantation. Indeed, patients who have echocardiographic evidence of LV dyssynchrony before CRT have better response rates. However, the presence of preimplantation LV dyssynchrony is not the only determinant of response because some patients with dyssynchrony before implantation still do not respond to CRT. It is currently unclear whether a reduction in LV dyssynchrony (LV resynchronization) after CRT implantation is mandatory for a positive response. The present study evaluates the effects of CRT on LV dyssynchrony and relates these effects to patient response in a group of patients with echocardiographic evidence of LV dyssynchrony (65 ms on tissue Doppler imaging). Our results show that LV resynchronization after CRT is an acute phenomenon. Despite the presence of substantial LV dyssynchrony before implantation, CRT that did not improve dyssynchrony immediately after implantation had a low likelihood of improvement during 6 months of follow-up. Thus, a reduction in LV dyssynchrony appears to be required for a favorable response to CRT. Potential explanations for a lack of LV resynchronization may include the presence of large areas of scar tissue throughout the left ventricle and suboptimal position of the LV pacing lead.

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