François Tournoux, M.D.; Erwan Donal, M.D., Ph.D.; Christophe Leclercq, M.D., Ph.D.; Christian De Place, M.D.; Christophe Crocq, M.D.; Aude Solnon, M.D.; Alain Cohen-Solal, M.D., Ph.D.; Philippe Mabo, M.D.; Jean-Claude Daubert, M.D.

J Cardiovasc Electrophysiol.  2007;18(10):1022-1027.  ©2007 Blackwell Publishing

Abstract and Introduction

Abstract

Background: Cardiac resynchronization therapy (CRT) improves heart failure (HF) symptoms through a reduction of cardiac mechanical dyssynchrony. Mechanical dyssynchrony is currently estimated by electrical dyssynchrony (QRS duration). It is known that electrical and mechanical dyssynchrony are not well correlated in HF patients. However, there is limited information about whether this relationship might be influenced by the underlying cardiomyopathy.
Methods: Doppler echocardiography was performed in 88 patients presenting with heart failure due to ischemic (n = 42) or nonischemic (n = 46) heart disease, left ventricular ejection fraction <40%, New York Heart Association class II-IV, regardless of their QRS duration. Interventricular dyssynchrony was assessed by the time interval between preaortic and prepulmonary ejection times. Intraventricular dyssynchrony was ascertained by (1) the delay between the earliest and the latest peak negative longitudinal strain recorded in the basal and mid-segments of the lateral and septal walls (TMinMax) and (2) the standard deviation of time-to-peak in the same segments (SDdys).
Results: The correlation coefficient between QRS duration and mechanical interventricular dyssynchrony was r = 0.47 (P < 0.001) in patients with nonischemic disease and nonsignificant in patients with ischemic disease. Similarly, the correlation coefficient between QRS duration and mechanical intraventricular dyssynchrony was significant in patients with nonischemic disease (r = 0.37, P = 0.01 for TMinMax; r = 0.42, P = 0.003 for SDdys) and nonsignificant in patients with ischemic disease.
Conclusion: The concordance between electrical dyssynchrony assessed by QRS duration and mechanical dyssynchrony assessed by myocardial strain is dependent upon the underlying cardiomyopathy. This observation may improve our understanding of the various responses observed in CRT patients.

Introduction

The goal of cardiac resynchronization therapy (CRT) is to reduce cardiac mechanical dyssynchrony, thereby reducing the morbidity and mortality in heart failure (HF) patients with depressed left ventricular (LV) ejection fraction (EF) and who remain in New York Heart Association (NYHA) functional class III or IV despite optimal medical therapy.^[1-3] Mechanical ventricular dyssynchrony is estimated by electrical dyssynchrony, easily assessed with the QRS duration; a cut-off of 120 msec is used in the current guidelines^[4] to identify dyssynchrony.

However, while patients with either ischemic or nonischemic cardiomyopathy might benefit from CRT, up to 30% do not respond^[5] and evidence is mounting that, in the broad population of patients with HF of different etiologies, QRS duration is not a reliable marker of cardiac dyssynchrony.^[6,7] There is, however, a paucity of information regarding the influence of the etiology of heart disease on electromechanical correlates in chronic HF. The pathophysiologic mechanisms causing an increased QRS duration in ischemic and nonischemic cardiomyopathy may be dissimilar. In nonischemic patients, a wide QRS complex can generally be viewed as reflecting advanced myocardial disease.^[7] In dilated cardiomyopathy of ischemic origin, a wide QRS complex may appear not only at follow-up due to LV remodeling and dilation, but also during the acute phase of myocardial infarction,^[8,9] indicating focal ischemic processes interfering with impulse propagation. This second phenomenon might distort the relationship between QRS duration and mechanical dyssynchrony.

The objective of our study was to assess how the underlying cardiomyopathy (etiology and/or severity) may influence the relationship between electrical and mechanical cardiac dyssynchrony in a consecutive series of HF patients with ischemic or nonischemic heart disease.

Methods

Subjects

Patients referred for evaluation of the severity of their cardiomyopathy with LVEF < 40%, LV end diastolic diameter >55 mm, and New York Heart Association class II-IV were included in this study, regardless of the QRS duration. Each patient underwent Doppler echocardiography in the cardiac ultrasound laboratories of Pontchaillou Hospital (Rennes, France) and Lariboisière Hospital (Paris, France). No patient was excluded because of poor image quality. This study was in compliance with rules of the ethics committee of both recruiting medical centers. Informed consent was obtained from each patient.

Ischemic Versus Nonischemic Heart Disease

Following coronary angiography, ischemic heart disease was defined using the Felker classification.^[10] Patients without coronary lesions or with a single ≥70% coronary artery stenosis, unless located on the left anterior descending or left main coronary artery, were classified as having HF of nonischemic etiology. Patients with multiple coronary artery stenoses, or with high-grade stenoses of the left main or left anterior descending coronary arteries, were classified has having HF due to ischemic heart disease. No additional imaging techniques (nuclear imaging, magnetic resonance imaging, or contrast perfusion) to categorize the etiology of heart failure were performed unless clinically indicated.

Doppler Echocardiography

Standard four-window transthoracic echocardiography was performed using a Vivid 7 (General Electric, Milwaukee, WI, USA) equipped with a 2.5 MHz phased-array transducer. Apical four- and two-chamber views were acquired for the calculation of LVEF with the biplane method of disks. End-diastolic left ventricular diameter was measured on an M-mode line drawn in the parasternal long axis view. Pulsed Doppler was used to record right and left ventricular outflow tract ejection flows. We imaged the apical four-chamber views in color-tissue Doppler and stored five consecutive cardiac cycles on a magneto-optical disk for further analysis. The image sector was approximately 30°, as narrow as possible to maximize the frame rate (>140 frames/second). However, in patients with the largest ventricles, it was impossible to reach 140 frames/second with a view of the whole heart. In these extreme cases, each wall was scanned independently with an image sector adjusted for a frame rate range from 140 to 200 frames/second. The upper limit of 200 frames/second was determined to keep a narrow range of frame rates among the patients of the study.

Assessment of Dyssynchrony

Electrical dyssynchrony was ascertained by the width of the widest QRS complex, measured for each patient on a surface electrocardiographic recording, and considered as the electrical dyssynchrony value.

Mechanical dyssynchrony was estimated using Doppler echocardiography. Interventricular dyssynchrony was ascertained by the time interval between the preaortic and prepulmonary ejection times, as previously described. Intraventricular dyssynchrony was based on two indices: (1) the time delay between the earliest and the latest peak values of negative strain (active deformation) recorded in the basal and mid segments of lateral and septal walls in the four-chamber apical view (TMinMax) and (2) the standard deviation of the time-to-peak values of the same ventricular segments (SDdys). This method, described by Poerner et al.,^[11] looks at active deformation of the myocardium, in contrast with the techniques described previously by Yu et al.^[12,13] using velocities that may represent passive motion of the myocardium. For each studied segment, we initially determined the time interval measured from the beginning of the QRS complex to the peak value of strain within the analyzed cardiac cycle. To overcome even slight differences in heart rate, all temporal parameters were normalized by dividing by the square root of the cycle length.

Statistical Analysis

Continuous variables are presented as mean ± standard deviation. The correlation between mechanical dyssynchrony and QRS duration was performed using the Pearson R-coefficient value calculation, completed by a univariate linear regression analysis when the R-value was near 1. A t-test was performed to compare baseline data between ischemic and nonischemic groups. To assess how the severity of the cardiomyopathy may influence the relationship between electrical and mechanical dyssynchrony, patients were stratified into two groups regarding the level of LV remodeling (≤200 mL vs >200 mL). A P value <0.05 was considered significant. Statistical analyses were performed using Statview 5.0.1 (SAS Inc., Cary, NC, USA).

Results

Study Population

Between May and October 2005, 88 HF patients were enrolled in this study. Baseline characteristics are reported in Table 1 . The underlying heart disease was nonischemic in 46 and ischemic in 42 patients. The LVEF was <30% in 72% of patients and 45% were in NYHA class III or IV. While the NYHA functional class tended to be higher among patients with ischemic heart disease, the functional status objectively measured by maximal oxygen consumption was similar in both groups. Patients with ischemic heart disease were older than those with nonischemic disease. The two groups were otherwise similar, with a large range of QRS durations (135 ± 39 msec in nonischemic and 130 ± 38 msec in ischemic patients).

Reproducibility of the Doppler Echocardiographic Parameters

Intra- and interobserver coefficients of variability, tested on 15 randomly selected cases, are shown in Table 2 . Intra- and interobserver variabilities were smallest for pulsed Doppler measurements (the SD of the error was between 3.6 and 4.9% for intraobserver variability and between 4.9% and 6.1% for interobserver variability) and largest for tissue Doppler measurements (the SD of the error was 8.5% for intraobserver variability and 6.7% for interobserver variability).

Correlation Between Electrical and Mechanical Dyssynchrony

The degree of electrical and mechanical dyssynchrony was similar in both study groups ( Table 3 ). In the overall population, the correlation between QRS duration and mechanical dyssynchrony was statistically significant (P < 0.05). However, the relationship between electrical and mechanical dyssynchrony was weak for interventricular dyssynchrony (r = 0.33, P = 0.002) as well as intraventricular dyssynchrony (r = 0.31, P = 0.003 for SDdys, and r = 0.26, P = 0.02 for TMinMax).

When the population was divided according to the etiology of cardiomyopathy, the correlation between QRS duration and mechanical interventricular dyssynchrony was limited to patients with nonischemic heart disease (r = 0.47, P < 0.001, Figure 1). Similarly, the correlation between QRS duration and mechanical intraventricular dyssynchrony was significant only in the group of patients with nonischemic cardiomyopathy (r = 0.42, P = 0.003 for SDdys (Figure 2) and r = 0.37, P = 0.01 for TMinMax). Figure 3 displays one patient with an ischemic cardiomyopathy and one patient with a nonischemic cardiomyopathy; both had similar QRS durations but very different values of mechanical dyssynchrony.

Figure 1. 

Correlation between mechanical inter-ventricular dyssynchrony and QRS duration.

     

Figure 2. 

Correlation between mechanical intraventricular dyssynchrony and QRS duration. *SDdys = mechanical intraventricular dyssynchrony assessed by the standard deviation of time-to-peak values of basal and mid-segments in lateral and septal walls.

     

Figure 3. 

Example of one ischemic patient and one nonischemic patient with similar QRS duration but different values of mechanical dyssynchrony.

     

Dividing the patients into two groups based on the severity of left ventricle remodeling (LV end-diastolic volume ≤ vs > 200 mL), the correlation between mechanical and electrical dyssynchrony was stronger in the nonischemic patients with LVEDV >200 (r = 0.54, P = 0.009 for SDdys), compared with those with LVEDV ≤200 and weaker in the group of ischemic patients. Among patients who met current clinical criteria for CRT (NYHA class III or IV with ejection fraction <35%), nine had a QRS duration less than 120 msec. The small size of this subgroup did not allow further analyses.

Discussion

Electrical dyssynchrony (estimated by QRS width) is the only index of ventricular dyssynchrony currently validated for patient selection in the field of CRT. Despite this strategy, Lecoq et al.^[14] reported 27% of nonresponders to CRT at 6 months of follow-up. Various causes of nonresponse to CRT have been identified, such as suboptimal LV lead position^[15] or minimal mechanical dyssynchrony despite electrical dyssynchrony.^[16] Bader et al.^[6] had previously shown in a large population of HF patients discordance between mechanical and electrical dyssynchrony. Our study is the first to show the contribution of the underlying cardiomyopathy to this discordance. We found significantly different behavior between the two etiologies with a positive correlation among nonischemic patients and no correlation among ischemic patients. Although earlier studies indicated that CRT benefits patients presenting with either ischemic or nonischemic cardiomyopathy,^[17] our results are in accordance with more recent reports with longer patient follow-up suggesting that the type of underlying cardiomyopathy influences the degree of benefit conferred by CRT: in a substudy of the MIRACLE trial, St John Sutton et al.^[18] showed that the mean decrease in LV volumes at 6 months was significantly less among patients with ischemic than among patients with nonischemic cardiomyopathy. In addition, LV volumes returned toward baseline in ischemic patients, in contrast with nonischemic patients, in whom the benefit conferred by CRT on LV remodeling persisted throughout 12 months of follow-up. Using magnetic resonance imaging in a group of HF patients with QRS duration ≥120 msec, Zwanenburg et al.^[19] showed that the propagation of onset of myocardial shortening was consistently from septum to lateral wall in nonischemic patients, versus no consistent direction of propagation in ischemic hearts. In other words, in HF patients with clear electrical dyssynchrony, the pattern of mechanical dyssynchrony is much more consistent in nonischemic patients than in ischemic patients. Nonischemic cardiomyopathy generally affects the entire myocardium, and the QRS prolongation reflects the extent of fibrosis (thus the severity of HF) rather than specific abnormalities of impulse propagation.^[7] In end-stage HF, fibrosis becomes more diffuse and homogeneous, probably explaining the higher correlation between mechanical dyssynchrony and QRS duration among our patients with higher levels of remodeling (end diastolic volumes >200 mL). In contrast, a large proportion of the myocardium may be unaffected in patients with ischemic cardiomyopathy despite a wide QRS complex: selective ischemic injury to the specialized conduction system can prolong the QRS complex in the absence of diffuse fibrosis. In fact, in an animal ischemic model,^[20] impaired function in the border zone has been shown not to be linked to electrical factors, but to result from mechanical interaction between ischemic and normal myocardium. We expected to find a greater correlation between electrical and mechanical dyssynchrony in ischemic patients with diffuse fibrosis, as indicated by greater LV remodeling. However, in contrast to the nonischemic group, the relationship between electrical and mechanical dyssynchrony was weaker. There may be several explanations for this observation. More heterogeneous scar in ischemic cardiomyopathy^[21] may result in various patterns of myocardial activation, even among the patients with the greatest degree of remodeling. While electrical dyssynchrony can be estimated using various invasive^[22] or noninvasive techniques,^[23,24] QRS duration remains the simplest parameter available to measure electrical dyssynchrony. However, despite its widespread use in clinical practice, QRS duration may not accurately reflect electrical dyssynchrony because it may exclude abnormal late activation (small fragmented portions of the QRS complex may not be considered in the measure of the QRS duration). In addition, the ischemic patients were significantly older and, if some of them had a brief history of cardiovascular events with heterogeneous disease, others may have had a longer history of HF with more global LV remodeling. Finally, the Doppler echocardiography method used in our study examined myocardial strain, as opposed to earlier studies looking at myocardial velocity or displacement, which if used in our study, may have included passive motion and generated different results. Our method looked at the true deformation of the myocardium, but may have not fully represented the total LV mechanical dyssynchrony because there may be heterogeneous myocardial deformation, especially in ischemic cardiomyopathy, and only the septal and lateral walls were assessed in the our study.

The clinical relevance of mechanical dyssynchrony as a method of patient selection for CRT remains to be established. Earlier studies using tissue Doppler imaging examined dyssynchrony mainly in the longitudinal axis and observed a nonsignificant difference between patients with ischemic and nonischemic cardiomyopathy.^[25] However, recent experimental and clinical studies^[26,27] have emphasized the importance of assessing myocardial function in both the longitudinal and radial axes. Cardiac contraction is mainly radial. But in the subendocardium, which is more sensitive to ischemia, fibers are mostly oriented longitudinally.^[28] Therefore, our assessment of cardiac dyssynchrony might have been more accurate by combining longitudinal and radial measurements. The range of frame rates we used (140-200 Hz) gave us a temporal resolution of 5 to 8 msec. This resolution may have been unable to detect with accuracy the onset of LV activation (5-60 msec after the beginning of the QRS) or the exact time between the beginning of the QRS and the end of the global activation of the LV (85-110 msec).^[22] Moreover, our study was performed at rest and did not look at the severity and topography of scar in each patient. Recent publications using either dobutamine^[29] or exercise^[30] suggest that mechanical dyssynchrony may be dynamic. This may be especially important for the assessment of ischemic patients. Finally, if we used a measure of LV dyssynchrony looking at true deformation of the myocardium in order not to consider passive motion, we did not stratify patients regarding their degree of dyssynchrony. In fact, our observational study in a large population of HF patients, performed to further our understanding of the relationship between electrical activation and mechanical events, was not designed to examine the impact of CRT on dyssynchrony. However, a complementary study on a more specific population and including the impact of CRT would add useful information.

Conclusion

To conclude, the relationship between electrical and mechanical dyssynchrony is dependent on the underlying cardiomyopathy. While QRS duration may be used as an indicator of mechanical dyssynchrony in nonischemic patients, our data show that various patterns of mechanical dyssynchrony observed in ischemic disease make this index less reliable in patients with ischemic cardiomyopathy. However, many nonischemic as well as ischemic patients substantially benefit from CRT if selected based on QRS duration. The goal is then to find a more specific method to characterize the dyssynchrony pattern of each patient in order to reduce the number of nonresponders. Our results suggest that the etiology of cardiomyopathy should be integrated into the evaluation of mechanical and electric dyssynchrony of patients referred for CRT. Currently, there is no consensus on the tools and parameters that should be used, but a combined approach incorporating electrical and mechanical dyssynchrony indices appears very promising.

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Reprint Address

Pr Jean-Claude Daubert, M.D., Department of Cardiology, Hôpital Pontchaillou-CHU, 2, rue Henri Le Guilloux, 35033 RENNES cedex 09, France. Fax: 33-(0)-2-99-28-25-10; E-mail: jean-claude.daubert@chu-rennes.fr .