Author + information
- Received February 18, 2015
- Revision received June 25, 2015
- Accepted July 15, 2015
- Published online June 1, 2016.
- Brecht Steelant, MSca,
- Ivan Stankovic, MD, PhDa,
- Ine Roijakkers, MSca,
- Marit Aarones, MD, PhDb,
- Jan Bogaert, MD, PhDc,
- Walter Desmet, MD, PhDc,
- Svend Aakhus, MD, PhDb and
- Jens-Uwe Voigt, MD, PhDa,∗ ()
- aDepartment of Cardiology, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium
- bDepartment of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- cDepartment of Radiology, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium
- ↵∗Reprint requests and correspondence:
Prof. Dr. Jens-Uwe Voigt, Department of Cardiovascular Diseases, University Hospital Gasthuisberg, Catholic University Leuven, Herestraat 49, Leuven 3000, Belgium.
Objectives This study sought to investigate the influence of scar extent and location on the motion pattern of the left ventricle (LV) and its interaction with LV conduction delays.
Background Different echocardiographic parameters have been proposed to identify responders to cardiac resynchronization therapy based on the detection of LV mechanical dyssynchrony. However, the impact of infarct scar on the diagnostic performance of these parameters remains unknown.
Methods We included 11 healthy volunteers and 122 patients with normal and severely reduced function, wide and narrow QRS, as well as with and without infarct scar. Location and extent of infarct scar was defined by contrast-enhanced cardiac magnetic resonance. Influence of infarct scar on the motion pattern of the LV was examined by measuring direction and amplitude of apical rocking. The influence of scar on different echocardiographic dyssynchrony parameters was investigated.
Results Scar in the absence of conduction delay caused most apical rocking in the presence of 3 to 4 infarct segments. Pure apical infarction caused no rocking. In wide QRS patients without infarct scar, apical rocking was mainly dominated by the conduction delay, whereas in wide QRS patients with ischemic cardiomyopathy, this pattern was modulated by the scar. Apical rocking was inversely related to scar extent (r = −0.54, p < 0.05). Apical rocking was better associated with cardiac resynchronization therapy response than conventional dyssynchrony measurements.
Conclusions LV motion patterns are mainly dominated by conduction delays, but they are also modulated by infarct scar. Higher scar burden resulted in less pronounced apical rocking. Apical rocking is more strongly associated with cardiac resynchronization therapy response than with conventional echocardiographic parameters and may therefore be used as a screening parameter.
- cardiac resynchronization therapy
- conduction delay
- contrast-enhanced cardiac magnetic resonance
- myocardial infarction
Cardiac resynchronization therapy (CRT) has become an established treatment option for patients with heart failure (HF) and conduction delays (1–3). However, one-third of patients selected according to current guideline criteria do not respond to this therapy, suggesting the need for a better understanding of the underlying pathophysiology (1).
Current published reports provide conflicting evidence to which extent imaging can contribute to this understanding (4–8). Recently, our lab could show that the dissipation of myocardial contractile function into mechanical dyssynchrony can be demonstrated and measured by means of echocardiography, using apical rocking as a quantitative or qualitative parameter (9). Other studies confirmed that apical rocking is associated with CRT response (9–13). Apical rocking combines information on both temporal and regional imbalance of contractile forces and is therefore a parameter that describes motion and deformation patterns relevant in the field of resynchronization therapy (14).
CRT candidate selection is particular challenging in patients with ischemic cardiomyopathy (15). Conduction delays may occur due to an infarct and do not necessarily reflect the same mechanical changes that occur in a nonischemic bundle branch block. Besides that, the lack of recruitable myocardium in hearts with large scars is known as a limiting factor for CRT response (16,17).
The mechanical consequences of the interaction of scar and conduction delays are complex and not entirely understood. In this study we used apical rocking to investigate how the location and extent of infarct scar determines left ventricular (LV) motion patterns and how scar modulates the mechanical consequences of a conduction delay. We further tested the potential use of this information in the clinical setting of resynchronization therapy.
Eleven healthy volunteers (normal group) without any history of cardiovascular disease were examined to define the normal motion of the LV. The upper limit of the 95% confidence interval (CI) of apical rocking in this group was used to distinguish between normal and abnormal motion of the heart.
Furthermore, 71 patients with previous myocardial infarction but borderline LV function (infarct group) were investigated to characterize the impact of scar location and extent on the LV motion pattern.
Finally, 56 HF patients with left bundle branch block (LBBB) and with ischemic origin left bundle branch block (iLBBB) (n = 21) or without ischemic origin left bundle branch block (nLBBB) (n = 35) were examined to determine the difference between scar-related motion abnormalities and those due to conduction delays. All HF patients were eligible for CRT according to current guideline criteria, were implanted, and were seen 1 year after CRT for a follow-up examination. Patients with LV end-systolic volume decrease >15% during follow-up were regarded as responders (18).
Contrast-enhanced cardiac magnetic resonance
In the infarct and iLBBB group, patients had myocardial infarcts for at least 4 months after initial presentation. Contrast-enhanced cardiac magnetic resonance (CMR) was used to determine position and extent of myocardial scar with the use of a 1.5-T scanner (Intera, Philips Medical Systems, Best, the Netherlands). Briefly, 10 to 20 min after intravenous injection of 0.2 mmol/kg gadopentetate dimeglumine (Magnevist, Schering, Berlin, Germany), late-enhancement images were obtained. Extent and localization of scar was evaluated by blinded experienced cardiologists, using a 17-segment model of the LV. Each segment was scored as 0 = absence of hyperenhancement, 1 = hyperenhancement of 1% to 25% of LV wall thickness, 2 = hyperenhancement extending 26% to 50%, 3 = hyperenhancement extending 51% to 75%, and 4 = hyperenhancement extending 76% to 100%. In the following, the number of segments with segmental hyperenhancement score ≥2 were considered for determining scar extent.
All patients were examined in a left lateral decubitus position and were in sinus rhythm. Standard 2-dimensional and Doppler echocardiography was performed using a Vivid 7 ultrasound scanner (GE Vingmed Ultrasound, Horten, Norway). Color tissue Doppler imaging was acquired from apical 2-, 3-, and 4-chamber view (2CV, 3CV, and 4CV). Image loops of 3 consecutive heart beats were digitally stored for further off-line analysis. The mean frame rate for color tissue Doppler imaging was in the range of 110 frames/s and for gray-scale images 60 frames/s. Spectral blood flow Doppler-derived timing of aortic and mitral valve opening and closure was used to define cardiac time intervals.
An EchoPAC workstation (software version 7.0.1, GE Vingmed Ultrasound) was used for all off-line analyses.
Calculation of apical rocking
The principle of quantifying apical rocking by measuring apical transverse motion (ATM) has been described elsewhere (14). ATM was calculated separately for each apical imaging plane as the average of the integrated longitudinal myocardial velocity (i.e., up-and-down motion) traces from the 2 opposite apical segments of the apical cap (Figure 1A). The amplitude of ATM was determined during systole (ATM_4CVSys) as well as for the total cardiac cycle in each imaging plane (ATM_4CVTot). The true motion of the apex, in a plane perpendicular to the LV long axis, during the entire cardiac cycle (apical rocking) and during systole (Apical RockingSys), was then reconstructed by combining the in-plane rocking curves of the 3 apical image planes (Figure 1B). Intraobserver and interobserver variability for measuring apical rocking has previously been shown to be small between readings (14). A comparison with a speckle tracking–based approach is described in the Online Appendix (Online Figure 1).
Comparison of apical rocking and scar location and extent
To analyze the influence of scar on the motion of the LV, a bulls-eye representation of the CMR scar definition and the ATM loop were coregistered (Figure 2). If the vector of Apical RockingSys was pointing toward the infarct segments, apical motion was counted as being “toward the infarct.” Any other motion was scored as “away from the infarct.” The amplitude of Apical Rocking was compared with the location and extent of the infarct scar.
Conventional dyssynchrony parameters
We calculated the standard deviation of time-to-peak velocity in 12 mid and basal segments (Ts-SD12) (6), the difference of time-to-peak velocity between septal and lateral wall (SL-Del) (19), as well as the time difference in peak anteroseptal–to–posterior wall strain (Tε-Diff) (5). LV dyssynchrony was determined according to the original published cutoff values: Ts-SD12 ≥32.6 ms (6); SL-Del ≥60 ms (19); and Tε-Diff ≥130 ms (5).
Continuous variables are presented as mean ± SD. Student t test and Mann-Whitney U test were used to compare groups of unpaired data of Gaussian and of non-Gaussian distribution, respectively. Chi-square test was used for evaluation of categorical data. For multiple group comparison, analysis of variance test with Bonferroni correction was used. Pearson correlation was used to examine the linear association between 2 variables. Areas under the curves (AUC) of receiver-operating characteristics were compared using the DeLong method with Bonferroni correction. All statistical tests were 2-sided and assessed at the 5% significance level.
Characteristics of the study population are summarized in Table 1. From the HF patients with LBBB, 39 (70%) responded to CRT (Table 2). Responders and nonresponders did not differ in baseline New York Heart Association functional class, QRS width, or LV ejection fraction. During follow-up, LV ejection fraction improved significantly in responders (25 ± 9% vs. 40 ± 11%, p < 0.001), but not in nonresponders (25 ± 6% vs. 27 ± 8%, p = 0.42). LV end-systolic volume significantly decreased in the responders versus the nonresponders (−49 ± 19% vs. 3 ± 13%, p < 0.001). Patients having myocardial infarction (n = 6) in the posterolateral wall had a low response rate (33%) to CRT, whereas patients having an infarct in the septal or anteroseptal wall (n = 7) responded better to CRT (72%, p = 0.45).
In the infarct group, 852 of 1,207 LV segments (71%) were classified as normal (CMR score 0), 8 segments (0.7%) as having CMR score 1, 70 (5.8%) as having score 2, 98 (8.1%) as having score 3, and 179 (14.8%) having score 4. The median number of infarct segments per patient was 5 (interquartile range: 1 to 10). Apical infarcts were found in 20% of infarct patients, posterolateral infarcts in 27%, and 53% of the patients had infarcts in other regions.
Of 357 segments of the iLBBB group, 165 segments (46%) were scored as infarct segments. In particular, 73 segments (20%) had CMR score 1, 47 (13%) score 2, 18 (5%) had score 3, and 27 (8%) had score 4. The median number of infarct segments per patient was 4 (interquartile range: 1 to 10) and was not significantly different from the infarct group (p = 0.41).
Results are summarized in Table 2. Apical rocking could be measured in 132 study subjects (96% feasibility). In the normal group, Apical Rocking was very low (mean = 1.45 [95% CI: 1.24 to 1.70] mm). The upper limit, 1.7 mm, was used as the threshold to distinguish between apical rocking and noise.
Apical Rocking and ATM_4CVTot were also low in the infarct group and not significantly different from the normal group. In nLBBB patients, Apical Rocking and ATM_4CVTot were significantly higher than the normal, the infarct, and the iLBBB groups.
Infarct scar versus apical rocking
The occurrence of apical rocking in hearts with infarct scar but without conduction delays was studied in the infarct group with preserved ejection fraction. Apical rocking above the cutoff of 1.7 mm was found in 35 infarct patients (49%). In these patients, the systolic apical motion pointed away from the infarct scar and showed a biphasic response to scar extent, with a maximum Apical Rocking amplitude in the presence of 3 to 4 infarct segments (Figures 3 and 4A to 4E). Ten patients with strict apical infarction showed no relevant Apical Rocking (1.4 ± 0.2 mm) (Figure 4F).
The interaction of infarct scar and LBBB was investigated in the iLBBB group. Two patients with only minor scar (CMR score <2) were excluded from further analysis. In the majority of iLBBB patients, the apex moved away from the infarct during systole (14 vs. 5; p < 0.05). A significant inverse correlation was found between Apical Rocking and scar extent (r = −0.54; p = 0.0182) (Figure 5).
Assessment of mechanical dyssynchrony using conventional parameters
In the group of infarct patients without conduction delays, conventional dyssynchrony parameters showed a dyssynchrony higher than the published cutoff values (Table 3) in 13% to 37% of cases. Using the cutoff value of apical rocking (ATM_4CVSys > 1.5 mm ), only 2% of patients were classified as dyssynchronous.
Outcome after CRT
In HF patients with LBBB, conventional dyssynchrony parameters predicted response with an accuracy between 42% and 66% (Figure 6A). In conventional dyssynchrony parameters, receiver-operating characteristic analyses measured AUC between 0.53 and 0.60. In contrast, ATM_4CVSys had a receiver-operating characteristic AUC of 0.87 (95% CI: 0.78 to 0.97), which was significantly higher compared with the conventional dyssynchrony parameters (p < 0.01 vs. SL-Del, Ts-SD12, and Tε-Diff, respectively). ATM_4CVSys would have predicted CRT response with a sensitivity, specificity, and accuracy of 85%, 77%, and 82%, respectively.
A subanalysis of the iLBBB group alone showed a similar relation between conventional dyssynchrony parameters (AUC between 0.56 and 0.61) and ATM_4CVSys (AUC 0.81) (Figure 6B).
This study was designed to investigate how location and extent of infarct scar determines LV motion patterns and how scar modulates the mechanical consequences of a conduction delay. We further tested the potential use of this information in the clinical setting of resynchronization therapy.
In patients with normal or mildly reduced LV function and without conduction delays, nonapical infarct scars induced abnormal apical motion away from the infarct region during systole. The motion amplitude was highest in the presence of 3 to 4 infarct segments. In patients with reduced LV function and conduction delays, apical rocking was highest without infarct scar. Apical Rocking was significantly lower in patients with ischemic etiology and showed an inverse relation with the infarct extent.
In comparison with other echocardiographic parameters of LV mechanical dyssynchrony, apical rocking was less influenced by the infarct scar and was more related to CRT response.
LV motion patterns in infarct and LBBB
In patients with infarct scar, the mechanical effects of conduction delay and scar cannot be easily separated. Therefore, we studied first a group of infarct patients without conduction delay (infarct group). Our data showed that scar causes a regional imbalance of forces resulting in systolic motion of the apex away from the scar region. This is in concordance with earlier observations on longitudinal function in ischemic disease (20) and is supported by our finding that a pure apical infarct does not cause any apical motion (Figure 4F). Interestingly, limited scar of 3 to 4 segments affected LV motion patterns most, smaller and larger scar less (Figures 3 and 4A to 4E). We hypothesize that in larger scars, a higher load on remote segments may lead to a decrease in function and, consequently, a lower difference in deformation of the walls.
In nonischemic cardiomyopathy patients with LBBB (nLBBB group), we observed a dominant lateral longitudinal shortening during systole, which results in a motion of the LV apex toward the lateral wall. This finding is in concordance with previous studies on this topic (14,21,22), showing a characteristic motion of the apex toward the strongest wall.
Our observations in ischemic cardiomyopathy patients (iLBBB group) suggest that the mechanical effect of a conduction delay is modulated by the infarct scar. The typical motion pattern of a LBBB remains almost unaffected if the scar extent is small. In bigger scars, the effect of the dysfunctional myocardium becomes dominant over the LBBB-induced imbalance of forces. If the scar burden is high, apical motion becomes smaller again, independent of the presence of a LBBB (Figure 5). This behavior is advantageous if apical rocking is used to describe LV mechanical dyssynchrony in the context of CRT patient selection, because patients with high scar burden have been shown to respond less to therapy (23). Our observations contradict a previous study (24) that correlated mechanical LV dyssynchrony with infarct size. Zhang et al. (24), however, used timing differences and standard deviations of velocity peaks to measure dyssynchrony. Our data indicate that conventional echocardiographic parameters are less specific in the detection of resynchronizable motion patterns.
Detection of LV dyssynchrony
Apical rocking toward the lateral side during ejection describes a motion pattern specific for a LV with mechanical asynchrony due to LBBB (22). It can be conveniently expressed by a single number (ATM) (14) or can be even assessed by visual inspection (9). The information contained in apical rocking comprises a temporal and a regional function component (9,10). In contrast, most conventional echocardiographic dyssynchrony parameters assess accurately the dispersion of myocardial peak velocities and therefore lose the information about the regional sequence of functional events, which lowers the specificity for detecting mechanical dyssynchrony due to LBBB (23).
This interpretation is supported by the group of infarct patients without conduction delay, in whom conventional parameters were detected in 13% to 37% dyssynchrony, whereas ATM_4CVSys did so in only 2% (Table 3). A similar behavior was seen in CRT candidates. Conventional echocardiographic parameters performed worse in patients with ischemic cardiomyopathy, which is in concordance with recent studies (7,25). On the other hand, echocardiographic parameters that consider timing and localization of contraction event, such as septal flash (26) or antero-postero strain delay (27), show comparably good results as apical rocking. Interestingly, Popovic et al. (22) demonstrated a clockwise longitudinal rotation of the apex in the 4CV, which decreased in the presence of infarct scar and supported our findings. It is noteworthy, however, that our data are reconstructed from all 3 apical planes and therefore consider the true direction of apical rocking. We also showed for the first time a biphasic effect of infarct scar on the extent of apical motion.
In order to confirm our tissue Doppler-derived results, we compared them to speckle tracking data. The latter were often difficult to obtain due to clutter and near field artifacts, which impaired apical rocking tracking quality. Nevertheless, speckle tracking correlated with tissue velocity imaging derived apical rocking illustrating the robustness of the parameter (Online Appendix).
In conclusion, current data suggest that in particular parameters (echocardiographic or others) that reflect timing and regional distribution of myocardial contraction describe LV mechanical dyssynchrony best and may play a role for CRT candidate selection.
In our study, we combined data from 3 different patient groups with different etiology of disease to draw conclusions on the effect of scar and LBBB on LV motion. A controlled approach would require the random induction of infarct scar and/or LBBB, which would require an experimental animal model. Though, our findings are in concordance with other publications, the healthy control subjects of our study population are not age-matched due to difficulties in recruiting respective control subjects. However, we have previously shown that age is not relevant factor regarding the minor apical rocking of healthy hearts (14).
Our definition of response was based on the clear evidence of LV reverse remodeling. Clinical response and response in terms of minor LV ejection fraction changes, or improvement of New York Heart Association functional class was not validated. Nevertheless, our approach is in-line with many CRT studies with short time follow-up (6,28,29).
Failure to respond to CRT may not be only due to insufficient patient selection. Suboptimal lead placement or unfavorable pacemaker settings must also be considered. A remaining dyssynchrony after CRT device implantation may be indicative for this and several investigators have reported advantageous effects of pacemaker optimization procedures (17,30,31). Also in this study, all CRT patients underwent pacemaker optimization after implantation. Response, however, was evaluated conservatively based on the intention-to-treat.
The calculation of the predictive value of different selection parameters was based on short-term LV reverse remodeling rather than hard endpoints such as mortality. Because the results are meant to illustrate the susceptibility of different parameters to the existence of scar tissue, we believe that this approach is sufficient to serve the purpose for a clinically meaningful evaluation of a parameter, mortality data should be used (10).
Infarct scar induces abnormal motion patterns in the LV and complicates the interpretation of LV mechanical dyssynchrony. Apical rocking combines the detection of temporal and functional inhomogeneities and appears more accurate in the assessment of mechanical dyssynchrony than parameters that consider timing only. Consequently, in this study, apical rocking was strongly associated with CRT response among HF patients with both ischemic and nonischemic origin. Our findings support the use of parameters that combine timing and regional distribution of myocardial function for assessment of mechanical dyssynchrony of the LV in CRT candidates.
COMPETENCY IN MEDICAL KNOWLEDGE: Mechanical dyssynchrony reflects both conduction delays and regional dysfunction. If these can be distinguished, mechanical dyssynchrony might allow a better characterization of patient candidates for CRT.
TRANSLATIONAL OUTLOOK: This information provides a better understanding of the relationship among infarct scar, mechanical dyssynchrony, and response to CRT. However, because of the effectiveness of CRT, the adoption of this or other selection strategies to decrease nonresponse to CRT should be validated in large-scale trials with robust endpoints.
For supplemental material, please see the online version of this article.
This work is supported by a research grant of the University Hospitals Leuven. Dr. Stankovic has received a research grant from the European Association of Echocardiography. Dr. Voigt has received an onderzoekstoelage grant from the University of Leuven and holds a personal research mandate (No. 1832912) of the Flemish Research Foundation (FWO). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- apical transverse motion
- area under the curve
- confidence interval
- cardiac magnetic resonance
- cardiac resynchronization therapy
- chamber view
- heart failure
- ischemic origin left bundle branch block
- left bundle branch block
- left ventricle
- nonischemic origin left bundle branch block
- difference in time to peak velocity between septal and lateral wall
- time difference in peak anteroseptal–to–posterior wall strain
- standard deviation of time-to-peak velocity in 12 mid and basal segments
- Received February 18, 2015.
- Revision received June 25, 2015.
- Accepted July 15, 2015.
- American College of Cardiology Foundation
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