Cardiac resynchronization therapy (CRT) is a rapidly evolving treatment option for patients with drug-refractory heart failure. Large clinical trials have demonstrated the sustained benefit of CRT in patients with moderate-to-severe heart failure (New York Heart Association (NYHA) functional class III or IV), systolic dysfunction (left ventricular [LV] ejection fraction [EF] ≤35%), and a widened QRS complex (≥120 ms) (1- 4). Beneficial effects of CRT include the improvement in heart failure symptoms, exercise capacity, and LV systolic performance associated with a reduction in rehospitalization for heart failure and improved long-term survival compared with optimized medical therapy (1- 5).

Previous studies demonstrated that the predominant mechanism of benefit from CRT appears related to the presence of LV dyssynchrony and subsequent resynchronization after CRT (6- 10). The presence of baseline LV dyssynchrony may therefore be mandatory for response to CRT. Traditionally, the duration of the QRS complex on the surface ECG has been used as a marker of LV dyssynchrony (1- 4,11- 12). However, recent studies demonstrated that QRS duration is only a weak marker of LV dyssynchrony (13- 16). It was observed that 20% to 30% of patients with QRS duration ≥120 ms did not have LV dyssynchrony, which may (partially) explain the lack of response to CRT (13). Conversely, it was demonstrated that 20% to 50% of heart failure patients with a narrow QRS complex (<120 ms) may also exhibit LV dyssynchrony, and these patients may benefit from CRT (13- 15). At present, minimal data are available regarding the effects of CRT in heart failure patients with a narrow QRS complex. Accordingly, the objective of the current study was to evaluate the effects of CRT in heart failure patients with a narrow QRS complex and LV dyssynchrony. In addition, these effects were compared with results obtained in a control group of heart failure patients with wide QRS complex and LV dyssynchrony.

Consecutive heart failure patients with evidence of LV dyssynchrony (≥65 ms) on tissue Doppler imaging (TDI) who were scheduled for implantation of a CRT device were prospectively screened for inclusion into 2 groups based on the baseline QRS duration. The target sample size for each group was 33 patients, and enrollment was continued until the target sample for each group was met.

The first group consisted of 33 consecutive patients with a narrow QRS complex (<120 ms), LV dyssynchrony ≥65 ms, severe heart failure (NYHA functional class III to IV), and LVEF ≤35%. The number of consecutive heart failure patients with a narrow QRS complex who were screened with TDI for the presence of LV dyssynchrony ≥65 ms was 105. The second group served as a control group and included 33 consecutive patients with a wide QRS complex (≥120 ms), LV dyssynchrony ≥65 ms, severe heart failure (NYHA functional class III to IV), and LVEF ≤35%.

Patients with a recent myocardial infarction (<3 months) or decompensated heart failure were excluded. Before CRT implantation, clinical status (including NYHA functional class, quality-of-life score, and 6-min walking distance) and QRS duration were assessed. Two-dimensional echocardiography at rest was performed to calculate LV volumes and LVEF. Next, TDI was performed to evaluate LV dyssynchrony. The QRS duration was reassessed on the day after implantation. The extent of LV dyssynchrony was reassessed both on the day after implantation and at 6 months’ follow-up. Clinical status, LV volumes, and LVEF were reassessed at 6 months’ follow-up.

Evaluation of clinical status included assessment of NYHA functional class, quality-of-life score (using the Minnesota quality-of-life questionnaire), and exercise capacity using the 6-minute hall-walk test. The QRS duration was measured from the surface ECG using the widest QRS complex from leads II, V₁, and V₆. QRS duration was scored by 2 independent observers who were blinded to all other patient data.

Resting echocardiography was performed at baseline, on the day after implantation, and at 6 months follow-up. The LV dyssynchrony assessment using TDI was performed at baseline and repeated on the day after implantation. Patients were imaged in the left lateral decubitus position using a commercially available system (Vingmed Vivid Seven; General Electric-Vingmed, Milwaukee, Wisconsin). Images were obtained using a 3.5-MHz transducer at a depth of 16 cm in the parasternal and apical views (standard long- and short-axis and 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) were derived, and the LVEF was calculated from the conventional apical 2- and 4-chamber images using the biplane Simpson’s technique (17).

In addition to the conventional echocardiographic examination, TDI was performed to assess LV dyssynchrony. For TDI, color Doppler frame rates were >80 frames/s and pulse repetition frequencies were between 500 Hz and 1 KHz, resulting in aliasing velocities between 16 and 32 cm/s. The TDI parameters were measured from color-coded images of 3 consecutive heart beats by offline analysis. Data were analyzed using commercial software (Echopac version 5.0.1, General Electric-Vingmed).

To determine LV dyssynchrony, the sample volume (6 × 6 mm) was placed in the LV basal parts of the anterior, inferior, septal, and lateral walls (using the 4- and 2-chamber apical views), and per region the time interval between the onset of the QRS complex and the peak systolic velocity was derived (i.e., the electrosystolic delays). Left ventricular 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) (10). The analysis of peak systolic velocities was limited to the LV ejection period, and post-systolic peaks were excluded. The opening and closing of the aortic valve were measured from the pulsed-wave Doppler signals in the LV outflow tract and subsequently superimposed on the TDI curves to mark the LV ejection period (using the “event-timing” function on the Echopac echo analysis software). To ensure highly interpretable and reproducible TDI curves (and minimize artefacts), high frame rates are crucial. The highest possible frame rates were achieved by narrowing the 4-and 2-chamber apical TDI views down to the left ventricle (i.e., excluding the right ventricle and atria). Previously reported inter- and intraobserver agreements for assessment of LV dyssynchrony were 90% and 96%, respectively (13). Based on previous data, a cutoff value of 65 ms was used as a marker of LV dyssynchrony (10). All echocardiographic measurements were obtained by 2 independent observers without knowledge of the clinical status of the patient.

The LV pacing lead was inserted transvenously via the subclavian route. First, a coronary sinus venogram was obtained during occlusion of the coronary sinus using a balloon catheter. Next, the LV pacing lead was inserted in the coronary sinus with the help of an 8-F guiding catheter and positioned as far as possible in the venous system, preferably in the (postero-) lateral vein. The right atrial and right ventricular leads were positioned conventionally. When a conventional indication for an internal defibrillator existed, a combined device was implanted.

The CRT device and lead implantation were completed without major complications (Contak TR or Contak Renewal TR2/1/2/4, Guidant, Minneapolis, Minnesota; and Insync (Marquis) III or Sentry, Medtronic, Minneapolis, Minnesota). Two types of LV leads were used (Easytrak [Guidant] or Attain [Medtronic]).

Continuous data were expressed as mean ± SD and compared with the 2-tailed Student t test for paired and unpaired data when appropriate. Comparison of proportions was performed using the Fisher exact test. Linear regression analysis was performed to determine the relationship between QRS duration and LV dyssynchrony and LV dyssynchrony and percentage change in LV end-systolic volumes. For all tests a p value of <0.05 was considered to be statistically significant.

The data were analyzed using SPSS for Windows version 11.0.1 (SPSS Inc., Chicago, Illinois).

Thirty-three patients with a narrow QRS complex and LV dyssynchrony ≥65 ms were included (28 men, mean age 63 ± 11 years). Baseline patient characteristics are summarized in (Table 1).

Following CRT implantation, QRS duration showed a slight but significant increase from 110 ± 8 ms to 129 ± 21 ms (p < 0.001). The TDI demonstrated an immediate decrease in LV dyssynchrony from 102 ± 32 ms to 35 ± 29 ms (p < 0.001), indicating acute LV resynchronization (Figure 1), which remained unchanged at 6 months follow-up (44 ± 35 ms; p ≤ 0.001 vs. baseline; p = NS vs. immediately after implant). (Figure 2) shows an example of TDI recordings in a patient with a narrow (Figure 2A) and a wide (Figure 2B) QRS complex.

At 6 months’ follow-up, all clinical and echocardiographic parameters improved significantly (Figure 3). Mean NYHA functional class improved from 3.1 ± 0.3 to 2.2 ± 0.6 (p < 0.001). The Minnesota quality-of life score improved from 39 ± 18 to 25 ± 17 (p < 0.001). The 6-min walking distance significantly improved from 274 ± 133 m to 370 ± 119 m (p < 0.001). Of note, on a patient basis, 88% of patients showed a clinical response to CRT (defined as an improvement of ≥1 NYHA functional lass).

Echocardiography at 6 months’ follow-up revealed a significant improvement in LVEF (from 22 ± 6% to 30 ± 8%; p < 0.001) and significant LV reverse remodeling with a decrease in LV end-diastolic volume from 216 ± 78 ml to 189 ± 81 ml and a decrease in LV end-systolic volume from 174 ± 75 ml to 134 ± 64 ml (both p < 0.001) (Figure 3).

No correlation was observed between baseline LV dyssynchrony and percentage change in LV end-systolic volume at 6 months follow-up (y = −0.1x − 9; n = 33; r = 0.22; p = NS).

Thirty-three consecutive patients with wide QRS complex and LV dyssynchrony ≥ 65 ms were also included in the current study and served as a control group (25 men, mean age 67 ± 9 years). Baseline characteristics are summarized in (Table 1). Following CRT implantation, QRS duration decreased from 175 ± 22 ms to 150 ± 22 ms (p < 0.001). The day after pacemaker implantation, TDI demonstrated a reduction in LV dyssynchrony from 113 ± 30 ms to 34 ± 24 ms (p < 0.001) (Figure 1), indicating immediate LV resynchronization, which remained unchanged at 6 months follow-up (32 ± 32 ms p ≤ 0.001 vs. baseline and p = NS vs. immediately after implant). At 6 months’ follow-up, 91% of patients showed a clinical response to CRT.

At 6 months’ follow-up, clinical parameters had improved significantly. Mean NYHA functional class improved from 3.1 ± 0.3 to 2.0 ± 0.6 (p < 0.001). The quality-of-life score improved significantly from 42 ± 15 to 25 ± 15 (p < 0.001), and the 6-minute walking distance improved from 253 ± 124 m to 385 ± 119 m (p < 0.001).

Using echocardiography, a significant improvement in LVEF (from 21 ± 6% to 30 ± 9%; p < 0.001) and a significant decrease in LV volumes (LV end-systolic volume from 189 ± 60 ml to 144 ± 58 ml and LV end-diastolic volume from 238 ± 72 ml to 203 ± 66 ml; both p < 0.001) were observed. No correlation was observed between baseline LV dyssynchrony and percentage change in LV end-systolic volume at 6 months follow-up (y = 0.1x − 35; n = 33; r = 0.14; p = NS).

In (Table 1) the baseline characteristics of the patients with narrow versus wide QRS complex are compared. Apart from the difference in baseline QRS duration, no significant differences were observed in baseline clinical and echocardiographic parameters. In particular, baseline LV dyssynchrony was similar in both groups (102 ± 32 ms vs. 113 ± 30 ms; p = NS).

No significant correlation was observed between baseline LV dyssynchrony and baseline QRS duration, neither in patients with narrow baseline QRS complex (y = 0.7x + 21; n = 33; r = 0.18; p = NS) nor in patients with wide QRS complex (y = 0.2x + 86; n = 33; r = 0.11; p = NS) (pooled data presented in Figure 4A).

In patients with narrow QRS complex at baseline, QRS duration showed a significant increase following CRT implantation, whereas QRS decreased in patients with baseline QRS duration ≥120 ms. The change in QRS duration was significantly different between both groups (Table 2). In contrast, the reduction in LV dyssynchrony (resynchronization) following CRT implantation was comparable between both patient groups ((Table 2), Figure 4).

Similar to the situation before CRT implantation, no significant relation between the QRS duration and LV dyssynchrony could be assessed at 1 day after implantation (Figure 4B).

At 6 months follow-up, the magnitude of improvement in clinical parameters was not different between both patient groups. For example, NYHA functional class improved by 0.9 ± 0.6 in patients with narrow QRS compared with 1.1 ± 0.6 in patients with wide QRS. Also, the magnitude of improvement in LVEF and the extent of LV reverse remodeling were comparable (Table 2).

The effects of CRT in this pilot study including heart failure patients with narrow QRS complex (<120 ms) and LV dyssynchrony can be summarized as follows. Cardiac resynchronization therapy resulted in an immediate reduction in LV dyssynchrony, which was followed at 6 months by an improvement in clinical symptoms and LVEF with LV reverse remodeling. Moreover, the extent of LV resynchronization and the magnitude of clinical and echocardiographic improvement were comparable in a control group of patients with wide QRS complex and LV dyssynchrony.

Recent studies have indicated that the key mechanism of benefit from CRT is the resynchronization of LV contraction. It was demonstrated that patients with extensive LV dyssynchrony at baseline improved in clinical symptoms and LV function after CRT, whereas patients without baseline LV dyssynchrony did not improve (6- 10).

Traditionally, the duration of the QRS complex on surface electrocardiogram has been used as a marker of LV dyssynchrony, and consequently only patients with a wide QRS complex (>120 to 150 ms) were included in large trials (1- 4,11- 12). However, recent data indicated that the QRS duration does not adequately reflect LV dyssynchrony (13- 16,18), as illustrated also in the present study (Figure 3). The lack of a relation between QRS duration and LV dyssynchrony has been reported not only in patients with wide QRS complex but also in patients with narrow QRS complex. Moreover, various studies demonstrated that severe LV dyssynchrony may be present in 20% to 50% of patients with narrow QRS complex (13- 15,18), suggesting that CRT may also be beneficial in heart failure patients with narrow QRS complex and severe LV dyssynchrony. This is an important issue, because the majority of heart failure patients may not show prolongation of the QRS complex, and recent observations suggested that QRS widening to >120 ms may occur in only 30% of heart failure patients (19- 21). Therefore, the majority of the heart failure patients have a narrow QRS complex and are currently not eligible for CRT (19- 21).

However, preliminary data from 2 small studies suggested that heart failure patients with narrow QRS complex may benefit from CRT (22- 23). Turner et al. (22) studied only the acute effects of CRT in a group of 20 heart failure patients with a QRS duration of ≤120 ms. In these patients, CRT resulted in an acute hemodynamic improvement, particularly in patients with a pulmonary capillary wedge pressure >15 mm Hg (22). In addition, Achilli et al. (23) studied the effects of CRT in a group of 14 heart failure patients with a QRS duration of ≤120 ms and compared these effects with a control group of 38 heart failure patients with a QRS duration of >120 ms. All patients had evidence of LV dyssynchrony on M-mode echocardiography in combination with interventricular dyssynchrony. The authors demonstrated that the clinical and functional benefit was similar in heart failure patients with wide and narrow QRS complex (23).

In the present study, both the immediate and the mid-term effects of CRT were evaluated in a group of 33 consecutive heart failure patients with a narrow QRS complex (≤120 ms) and LV dyssynchrony as detected by TDI.

Immediately after CRT implantation, a significant reduction in LV dyssynchrony was observed, indicating LV resynchronization. This reduction in LV dyssynchrony was comparable between patients with narrow and wide QRS complex, which is an important observation because recent studies indicated that resynchronization of LV dyssynchrony is the predominant mechanism underlying benefit from CRT (6- 10).

At 6 months follow-up, clinical status improved significantly as evidenced by improvement in NYHA class, quality-of-life score, and 6-min walking distance. Importantly, the magnitude of benefit was comparable between patients with narrow and wide QRS complex. The clinical improvement was associated with an improvement in LV systolic function and a reverse LV remodeling. These findings clearly indicate the beneficial effects of CRT in patients with narrow QRS complex.

Of note, the magnitude of beneficial effects was not different from patients with wide QRS complex.

Various limitations need to be addressed. Patients with narrow QRS complex but without LV dyssynchrony (<65 ms) on TDI were not included in the present study. Recent studies in patients with QRS duration ≥120 ms have indicated that patients without LV dyssynchrony at baseline did not benefit from CRT (6,10). In addition, a control group of narrow QRS patients without CRT was not included and needs to be evaluated in future studies. In addition, the current findings need confirmation in larger studies. Moreover, whether CRT will improve survival in heart failure patients with narrow QRS complex remains to be determined.

In the present study, LV dyssynchrony was assessed from 4 basal LV segments (10), however evaluation of more segments may further improve accurate assessment of LV dyssynchrony.

Also, color-coded TDI measures the velocity of the myocardium, which may not always equal active myocardial contraction. Other echocardiographic techniques, e.g., strain and strain rate imaging, can discriminate between active and passive myocardial motion. Large, comparative studies are needed to define which technique is most accurate in assessment of LV dyssynchrony.

Finally, the importance of posterolateral scar formation for response to CRT has recently been demonstrated (24). The presence of posterolateral scar tissue may be one of the explanations for the lack of improvement in patients despite the presence of baseline LV dyssynchrony. In the present study, however, data on scar tissue were not systematically available.

Cardiac resynchronization therapy has comparable effects in heart failure patients with narrow QRS complex as in patients with wide QRS complex in terms of LV resynchronization, improvement in clinical symptoms, LVEF, and LV reverse remodeling. These beneficial effects need confirmation in studies with larger populations.