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Recoordination Rather than Resynchronization Predicts Reverse Remodeling after Cardiac Resynchronization Therapy
Recoordination Rather than Resynchronization Predicts Reverse Remodeling after Cardiac Resynchronization Therapy Chun-Li Wang, MD, Chia-Tung Wu, MD, Yung-Hsin Yeh, MD, Lung-Sheng Wu, MD, Chi-Jen Chang, MD, Wan-Jing Ho, MD, Lung-An Hsu, MD, PhD, Nazar Luqman, MD, and Chi-Tai Kuo, MD, Taoyuan, Taiwan; Bander Seri Begawan, Brunei Darussalam
Background: Mechanical discoordination as studied by magnetic resonance imaging has been shown to be a better predictor of left ventricular (LV) reverse remodeling after cardiac resynchronization therapy (CRT) compared with mechanical dyssynchrony. Materials and Methods: This study assessed the value of acute recoordination derived from speckle-tracking echocardiography for predicting response to CRT compared with acute resynchronization. Thirty patients with heart failure scheduled for CRT were studied at baseline, immediately after CRT, and after 6 months of CRT. Acute recoordination after CRT was indexed by an acute reduction in radial discoordination index (RDI), defined as the ratio of average myocardial thinning to thickening during the ejection phase. Results: CRT responders were defined as those patients whose LV end-systolic volume decreased by $ 15% at the 6-month follow-up. Immediately after CRT, the responders (n = 18) demonstrated a significant reduction in RDI (P < .001), which was sustained at the 6-month follow-up (P < .001). The nonresponders, however, did not show a significant change in RDI after CRT. LV reverse remodeling at the 6-month follow-up was significantly correlated with acute recoordination (r = 0.75, P < .001) but weakly correlated with acute resynchronization (r = 0.43; P = .02). Conclusions: Receiver operating characteristic analysis revealed that acute recoordination provided the best separation for prediction of CRT responders compared with acute resynchronization, baseline dyssynchrony, or baseline discoordination. LV recoordination after CRT is an acute phenomenon and predicts response to CRT at 6-month follow-up better than resynchronization. (J Am Soc Echocardiogr 2010;23:611-20.) Keywords: Cardiac resynchronization therapy, Discoordination, Dyssynchrony, Echocardiography, Speckle tracking
Cardiac resynchronization therapy (CRT) has proven helpful in patients with heart failure and a wide QRS complex.1 Despite its efficacy, 30% to 40% of patients do not benefit from CRT.2 Several studies suggested that mechanical dyssynchrony is a potential tool to identify CRT responders.3-7 In addition, immediate reduction in left ventricular (LV) dyssynchrony after CRT was thought to predict LV reverse remodeling at 6-month follow-up.8 However, the Predictors of Response to CRT (PROSPECT) study showed disappointing results on the use of mechanical dyssynchrony in predicting response to CRT.9 From the First Division of Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan (C.L.W., C.T.W., Y.H.Y., L.S.W., C.J.C., W.J.H., L.A.H., C.T.K.); College of Medicine, Chang Gung University, Taoyuan, Taiwan (C.L.W., C.J.C., W.J.H., L.A.H., C.T.K.); and Department of Cardiology, RIPAS Hospital, Bander Seri Begawan, Brunei Darussalam (N.L.). Reprint requests: Chi-Tai Kuo, MD, First Division of Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, 5, Fushin Street, Kweishan Hsiang, Taoyuan, Taiwan (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2010 by the American Society of Echocardiography. doi:10.1016/j.echo.2010.03.012
In a recent study using circumferential strain by magnetic resonance imaging, Kirn et al10 demonstrated that mechanical discoordination (opposite strain within the LV wall) predicted reverse remodeling after CRT better than mechanical dyssynchrony. In the present study, we hypothesize that LV recoordination rather than resynchronization is a better approach to predict response to CRT. A novel approach to detect LV recoordination with speckletracking echocardiography was evaluated for predicting CRT response compared with resynchronization derived from classic dyssynchrony metrics. Immediate LV recoordination after CRT was indexed by an acute reduction in radial discoordination index (RDI), defined as the ratio of average myocardial thinning to thickening during the ejection phase.
MATERIALS AND METHODS Patients Consecutive patients with heart failure scheduled for CRT implantation were enrolled. The selection criteria for CRT included moderate to severe heart failure (New York Heart Association functional class III and IV) despite optimal medical therapy, LV ejection 611
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Abbreviations
AS-P delay = Time difference between the anteroseptal and posterior segments CRT = Cardiac resynchronization therapy EF = Ejection fraction LV = Left ventricular MD-6 = Time difference between the earliest and latest segments of 6 segments
PROSPECT = Predictors of Response to CRT study
RDI = Radial discoordination index RDI-B = 6 basal LV segments
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fraction (EF) # 35%, and QRS duration > 120 ms. Two agematched groups with narrow QRS (duration < 120 ms) served as controls: 1) patients without structural heart disease and with a normal echocardiogram (normal group) and 2) patients with LV EF < 35% (low EF group). Patients’ clinical status, LV volumes, and EF were assessed before CRT implantation and after 6 months of CRT. LV dyssynchrony and discoordination were assessed at baseline, immediately after CRT, and at a 6-month followup. Each parameter was measured from 3 consecutive beats and averaged for purpose of analysis.
Table 1 Clinical characteristics Narrow QRS control groups
Age (y) Female, n (%) Ischemic cause, n (%) LV EF (%) LV EDV (mL) QRS duration (ms)
Echocardiography Subjects were imaged in the left lateral decubitus position with a commercially available system (Vivid 7, General Electric Vingmed Ultrasound, Horten, Norway). Standard 2-dimensional and color Doppler data triggered to the QRS complex were saved in cineloop format. The LV volumes and EF were measured from the conventional apical 2- and 4-chamber images using the biplane Simpson method. The severity of mitral regurgitation was evaluated by color jet area and as percent jet area relative to left atrial size. Patients with a reduction of $ 15% in LV end-systolic volume at the 6-month follow-up were considered CRT responders. LV dyssynchrony and discoordination were evaluated by speckletracking echocardiography from the parasternal short-axis views at the level of papillary muscles and mitral valve. Gain settings and imaging width were adjusted to optimize the gray scale (frame rate of 50-80 hertz) and not to compromise the image resolution. Each time, we analyzed a single beat and the gating was set to begin with the onset of the QRS complex. End systole was chosen as the single frame for marking the region of interest to include the maximal wall thickness for strain analysis. The inner marker was traced to the endocardial-cavity interface at end systole, and the outer marker was traced to the LV epicardium to obtain reproducible time–strain curves.12,13 The software (EchoPac 6.1, General Electric Vingmed Ultrasound) automatically tracked the image speckle and produced 6 regional radial strain and strain rate curves. The region of interest
Low EF (n = 40)
CRT group (n = 30)
P
65 6 9 9 (45) 0 (0) 64 6 9 79 6 19 91 6 8
67 6 8 19 (48) 20 (50)* 26 6 6* 163 6 60* 95 6 11
69 6 10 18 (60) 12 (40)* 23 6 8* 172 6 65* 166 6 23*,†
.22 .48 .001 <.001 <.001 <.001
EF, Ejection fraction; CRT, cardiac resynchronization therapy; LV, left ventricular; EDV, end-diastolic volume. *P < .001 vs normal group. † P < .001 vs low EF group.
Table 2 Clinical characteristics at baseline and 6 months after cardiac resynchronization therapy Nonresponders (n = 12)
RDI-M = 6 mid-LV segments Cardiac Resynchronization RDI-12 = 12 LV segments Therapy Procedure RS-SD = Standard deviation The pacing leads were posiof times to peak strain for 6 tioned at the right ventricular segments apex or mid-septum, at the right atrial appendage, and in the posterior or posterolateral branch of coronary vein. The atrioventricular interval was optimized using the established method to ensure adequate LV filling.11 No adjustments were made to the interventricular interval before the 6-month follow-up. The local ethics committee approved the study protocol, and all subjects gave informed consent.
Normal (n = 20)
Age (y) Female, n (%) Ischemic cause, n (%) QRS duration (ms) Medication, n (%) ACE inhibitors/ARB B-blockers Diuretics NYHA class Baseline 6 months LV EDV (mL) Baseline 6 months LV ESV (mL) Baseline 6 months LV EF (%) Baseline 6 months Mitral regurgitation (%) Baseline 6 months
67 6 11 6 (50) 8 (67) 170 6 29
Responders (n = 18)
P
71 6 8 12 (67) 4 (22) 164 6 20
.24 .36 .02 .47
17 (94) 16 (89) 12 (57)
1.0 1.0 .70
3.2 6 0.3 2.6 6 0.7†
3.1 6 0.3 1.5 6 0.5*
.65 <.001
194 6 75 209 6 90
158 6 55 101 6 33*
.14 .002
156 6 72 171 6 83
121 6 48 56 6 24*
.12 .001
21 6 8 21 6 8
24 6 7 46 6 8*
.37 <.001
22 6 10 20 6 10
24 6 12 8 6 5*
.68 .003
11 (92) 10 (83) 9 (75)
ACE, Angiotensin-converting enzyme; ARB, angiotensin receptor blockers; NYHA, New York Heart Association; LV, left ventricular; EDV, end-diastolic volume; ESV, end-systolic volume; EF, ejection fraction. Values are mean 6 standard deviation or number (percentage). *P < .001 vs baseline. † P = .008 vs baseline.
was redrawn if tracking quality was poor or the curves were viewed to be inadequate. Radial Dyssynchrony and Discoordination Analysis The data of radial strain and strain rate were exported to a spreadsheet program (Microsoft Excel, Microsoft Corp, Seattle, WA) to calculate dyssynchrony and discoordination. The time to peak strain
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Table 3 Discoordination and dyssynchrony measurements in control groups and cardiac resynchronization therapy group Narrow QRS control groups
RDI-B RDI-M RDI-12 AS-P delay RS-SD MD-6
CRT group
Normal (n = 20)
Low EF (n= 40)
All CRT patients (n = 30)
Nonresponders (n = 12)
Responders (n = 18)
1 (0, 2)* 1 (0, 1)* 1 (0, 1)* 53 (28, 78)* 28 (20, 39)* 62 (48, 85)*
11 (6, 19)† 18 (10, 30)* 15 (8, 22)* 118 (75, 180)* 90 (58, 129)* 227 (125, 310)*
16 (7, 59) 58 (37, 115) 30 (15, 69) 305 (189, 353) 175 (131, 198) 371 (306, 470)
17 (9, 38) 36 (10, 163) 18 (11, 58) 192 (110, 318) 120 (78, 181) 292 (191, 435)
14 (2, 62) 70 (51, 115)‡ 32 (18, 78) 326 (193, 354)‡ 174 (130, 202)‡ 365 (305, 466)
RDI, Radial discoordination index; EF, ejection fraction; RDI-B, RDI derived from 6 basal LV segments; RDI-M, RDI derived from 6 mid-LV segments; RDI-12, RDI derived from 6 basal-LV and 6 mid-LV segments; AS-P delay, anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments. Values are median (first, third quartiles). *P < .001 vs all CRT patients. † P < .05 vs all CRT patients. ‡ P < .05 vs baseline nonresponders.
from each of the 6 mid-LV segments was measured. Dyssynchrony indices were defined as the time difference between the anteroseptal and posterior segments (AS-P delay), the standard deviation of times to peak strain for 6 segments (RS-SD), and the time difference between the earliest and the latest segments of the 6 segments (MD-6).4,14 The immediate resynchronization was defined as the percentage difference between preimplantation LV dyssynchrony and the one at immediate follow-up.8 The radial strain rate signals from the 6 segments were split into positive signals ep(t) and negative signals en(t). Averaging ep(t) and en(t) over 6 basal-LV or mid-LV signals resulted in average myocardial thickening and thinning, respectively. Integration of these signals in the ejection phase resulted in a positive strain ep, representing the amount of myocardial contraction, and a negative strain en, representing the amount of myocardial thinning. The timing of ejection phase (between aortic valve opening and aortic valve closure) was determined from the Doppler velocity signal at the LV outflow tract. RDI was calculated as a ratio of the amount of average myocardial thinning relative to the amount of average myocardial thickening (denominator) during the ejection phase.10 The RDI was measured from 6 basal LV segments (RDI-B), 6 mid-LV segments (RDI-M), and 12 (ie, 6 basal and 6 mid) LV segments (RDI-12). The difference between the preimplantation RDI and the RDI at immediate follow-up defined the acute recoordination. Statistical Analysis Data were expressed as mean 6 standard deviation for continuous variables and as absolute frequencies and relative percentages for categoric variables. Continuous variables were compared by means of 1-way analysis of variance for overall comparison and the Dunnett test for post hoc comparisons. The chi-square test with the Fisher exact test (if necessary) was used to compare categoric variables. Dyssynchrony and discoordination indices were summarized with the median and 25th and 75th percentiles and compared with the Mann–Whitney test for each pair of groups. Changes over time within a group were analyzed by the Friedman test and Wilcoxon test for post hoc comparisons. The Pearson correlation analysis was performed to determine the relationship between acute recoordination/resynchronization and reverse remodeling at the 6-month follow-up. Receiver operating characteristic analysis was used to determine the optimal cutoff value of the variables for prediction of re-
sponse to CRT.13 Reproducibility was tested using the Bland–Altman method. For all tests, a value of P < .05 was considered statistically significant.
RESULTS Baseline variables of the studied patients are summarized in Tables 1 and 2. All patients who received CRT survived during the 6-month follow-up. Nonresponders were similar to responders in all aspects, except for greater prevalence of ischemic cardiomyopathy. Both groups improved clinically, as indicated by the decrease in New York Heart Association class. However, after 6 months of CRT the LV volumes and mitral regurgitation decreased and LV EF increased in the responders only. Comparisons of Baseline Dyssynchrony and Discoordination Comparisons of dyssynchrony and discoordination indices among control and CRT groups are shown in Table 3. All indices differed significantly between control and CRT groups. Significant differences were present between nonresponders and responders in baseline RDI-M, AS-P delay, and RS-SD. Figures 1 and 2 show baseline dyssynchrony and discoordination analyses in a normal subject, a nonresponder, and a responder. In the normal subject, all midventricular segments contracted synchronously and the peak strain of each segment occurred almost simultaneously after the end of ejection phase (Figure 1). During the ejection phase, myocardial thickening was dominant and myocardial thinning was negligible. In the responder, peak radial strain occurred before the ejection phase in 3 early contracted segments (Figure 2). These early contracted segments developed myocardial thinning that was indicated by the negative strain rate during the ejection phase. Similarly, the strain analysis in the nonresponder showed a comparable measure of dyssynchrony by calculating the time-to-peak difference between the early and late contracted segments. However, in the nonresponder, the early peak strain occurred later at the early ejection phase with a smaller peak value and in fewer segments compared with the responder. Therefore, the amount of myocardial thinning relative to myocardial thickening during the ejection phase was smaller than that of the responder.
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show a significant change after CRT. In contrast, all indices differed significantly after CRT in the responders. In the post hoc comparisons, all indices demonstrated a significant reduction immediately after CRT. At the 6-month follow-up, the reductions in RDI and all dyssynchrony indices by CRT were still present. Figure 3 presents the individual values of RDI-M and AS-P delay before and after CRT. The baseline RDI-M values of the responders and nonresponders were widely separated. The responders had a medium to high value (35%-160%) that consistently decreased immediately after CRT (P < .001). In contrast, the nonresponders had a low (<40%) or high RDI-M (>200%) value that increased or did not decrease sufficiently at the immediate follow-up (Figure 3A). The values of AS-P delay showed substantial reductions immediately after CRT in most of the responders but also in some of the nonresponders (Figure 3B). Figure 4 shows representative strain and strain rate changes in a responder. In the responders, the early contracted segments, usually anteroseptal and inferoseptal walls, reached early peak strains before the onset of ejection phase. These early contracted segments developed positive strain rates before the ejection phase and mostly negative strain rates during the ejection phase. Immediately after CRT, the early peak strains disappeared and were replaced by small and late systolic peak strains near the end of ejection phase. As a result, the myocardial thinning of the early contracted segments diminished and RDI-M reduced immediately after CRT. The AS-P delay also decreased because of the disappearance of the early peak strain. After 6 months of CRT, LV function and discoordination improved as indicated by the increased peak strains in all segments and a reduced value of RDI-M. Table 5 shows the relationships between acute recoordination/resynchronization and reverse remodeling. LV reverse remodeling was significantly correlated with acute recoordination (RDI-M, r = 0.75, P < .001) but weakly correlated with acute resynchronization (AS-P delay, r = 0.43, P = .02). Receiver operating characteristic analysis (Figure 5) revealed that acute recoordination provided the best separation for prediction of CRT responders compared with acute resynchronization, baseline dyssynchrony, or baseline discoordination (acute RDI-M reduction > 20%: sensitivity 100%, specificity 91%; acute RDI-12 reduction > 10%: sensitivity 94%, specificity 100%). RDI-M was the only baseline index that was useful for prediction of responders (area under curve 0.73, cutoff value of the baseline RDI-M > 40%; sensitivity 94%, specificity 67%). Figure 1 Dyssynchrony indices and RDI-M in a normal control. Tracings of strain and strain rate of 6 mid-ventricular segments are represented as colored lines. The time course of the average thickening [ep(t)] and average thinning [en(t)] are represented as a solid black line and a dashed black line, respectively. The amount of myocardial thickening (ep) and thinning (en) during the ejection phase are represented with the area below curve ep(t) and above curve en(t) (zero in this subject), respectively. RDI-M was calculated as -(en/ep)100%. During the ejection phase, the amount of average myocardial thickening was dominant and the amount of average myocardial thinning was negligible. AS-P delay, Anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments.
Recoordination and Resynchronization after Cardiac Resynchronization Therapy Table 4 shows index changes over time after CRT. In the nonresponders, all discoordination and dyssynchrony indices failed to
Subgroup Analysis for Ischemic Cause Patients with ischemic cardiomyopathy have lower baseline discoordination than patients with nonischemic dilated cardiomyopathy (median RDI-M, 38% vs 72%, P = .02; median RDI-12, 17% vs 38%, P = .05). In patients with ischemic cardiomyopathy, acute recoordination provided the best separation for prediction of response compared with acute resynchronization, baseline dyssynchrony, and baseline discoordination (acute RDI-M reduction > 20%: area under the curve 0.91, sensitivity 100%, specificity 87%; acute RDI-12 reduction > 8%: area under the curve 0.91, sensitivity 100%, specificity 87%). Reproducibility Reproducibility was tested in a random selection of 20 patients with CRT at baseline and immediate follow-up. The interobserver and intraobserver variability of RDI were 9% 6 11% and 7% 6 12% for RDI-B, 11% 6 12% and 10 6 11% for RDI-M, and 10% 6 16% and 7% 6 10% for RDI-12, respectively. Variability of RDI seemed to be related to degree of discoordination in individual patients
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Figure 2 Baseline dyssynchrony indices and RDI-M in a nonresponder and responder. Despite a comparable measure of dyssynchrony, discoordination analysis reveals a smaller amount of RDI-M in the nonresponder compared with the responder. AS-P delay, Anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments. (Figure 6). Close agreement was observed when lesser degrees of discoordination were present (RDI < 50%). However, variability of RDI increased as the degree of radial discoordination increased, in particular RDI > 100%. Limits of agreement on Bland–Altman analysis ranged from 24% to 33%.
DISCUSSION This study shows that RDI, an index of mechanical discoordination, performs better than indices of mechanical dyssynchrony in discriminating responders and nonresponders, and in detecting a substantial
immediate decline mostly in responders. Acute recoordination correlates better with reverse remodeling after 6 months of CRT than acute resynchronization. These findings support the notion that mechanical discoordination reflects the reserve contractile capacity that can be recruited by CRT and is a key target for long-term CRT benefits.10 A comprehensive assessment of abnormal LV mechanics caused by asynchronous activation can be quantified by means of internal stretch fraction or RDI.10 In left bundle branch block, the septal wall is activated early, whereas the lateral and posterior walls are activated late.15 The asynchronous activation leads to early septal and late posterior–lateral contraction. Early septal contraction causes posterior–lateral thinning or stretching, followed by late posterior–lateral contraction
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Table 4 Changes of discoordination and dyssynchrony indices after cardiac resynchronization therapy Nonresponders (n = 12)
RDI-B (%) RDI-M (%) RDI-12 (%) AS-P delay (ms) RS-SD (ms) MD-6 (ms)
Responders (n = 18)
Baseline
Immediate
6 mo
P
Baseline
Immediate
6 mo
P
17 (9, 38) 36 (10, 163) 18 (11, 58) 192 (110, 318) 120 (78, 181) 292 (191, 435)
18 (2, 71) 58 (31, 125) 33 (10, 75) 124 (78, 299) 108 (80, 173) 218 (167, 379)
11 (4, 37) 54 (29, 218) 35 (11, 49) 157 (77, 393) 107 (92, 218) 258 (223, 440)
.08 .21 .78 .17 .78 .47
14 (2, 62) 70 (51, 115) 32 (18, 78) 326 (193, 354) 174 (130, 202) 365 (305, 466)
5 (2, 7)* 10 (3, 17)* 7 (4, 11)* 109 (69, 188)* 71 (50, 146)* 152 (114, 321)*
3 (1, 4)*,‡ 2 (1, 4)*,† 3 (1, 4)*,† 76 (14, 111)*,† 50 (11, 75)*,† 117 (28, 162)*,†
.001 <.001 <.001 <.001 <.001 <.001
RDI, Radial discoordination index; EF, ejection fraction; RDI-B, RDI derived from 6 basal LV segments; RDI-M, RDI derived from 6 mid-LV segments; RDI-12, RDI derived from 6 basal-LV and 6 mid-LV segments; AS-P delay, anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments. *P < .01 vs baseline. † P < .01 versus immediate. ‡ P < .05 versus immediate.
Figure 3 Changes of RDI-M (A) and AS-P delay (B) after CRT in responders and nonresponders. Responders had a medium to high value of RDI-M, which consistently reduced after CRT. Mechanical dyssynchrony reduced significantly after CRT in the responders but also in some of the nonresponders. AS-P delay, Anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments.
causing septal thinning or stretching. The internal stretch or thinning leads to energy wasting and a decline in efficiency of myocardial contraction.10,16 CRT can reverse the adverse mechanical consequences by synchronizing LV activation and contraction. Patients who exhibit acute recoordination will respond to CRT, whereas patients who have a low level of baseline discoordination or an insufficient improvement in discoordination usually do not respond to CRT. Our results are consistent with a prior study that showed an index of mechanical discoordination (opposite strain within the LV wall) was superior to indices of mechanical dyssynchrony at predicting response to CRT.10 Mechanical dyssynchrony refers simply to the timing of peak or onset of contraction. Kirn et al10 used circumferential strain from magnetic resonance imaging to quantify baseline discoordination and mechanical dyssynchrony in 160 sites, covering 70% of the LV wall. Our findings suggest that baseline discoordination by measuring only mid-LV radial strain rate was useful for predicting response to CRT. RDI-M showed an almost equivalent ability with RDI-12 in identifying CRTresponders. Adding basal-LV segments into the analysis may yield more comprehensive LV functional assessment but did not improve the ability of prediction of CRT responders. Evaluation of LV dyssynchrony and discoordination using speckletracking analysis is feasible in all 3 deformation types: radial, circumferential, and longitudinal strain.17 Using radial strain to assess dyssynchrony or discoordination is sensible because the ratio of thinning to thickening is usually high, indicating a better signal to noise ratio compared with longitudinal and circumferential strain. In addition, Delgado et al14 showed that among the 3 deformation types, only baseline dyssynchrony assessed with radial strain (both AS-P delay and RSSD) was able to identify potential CRT responders. This pilot study found that discoordination assessed with radial strain rate was useful for identifying CRT responders. Further study is needed to establish the feasibility and value of applying speckle-tracking analysis of recoordination with longitudinal and circumferential strain.17 Previous studies have reported the effect of CRT on LV dyssynchrony,5,8,18-20 most of which showed immediate reduction in dyssynchrony after CRT.5,8,18 For instance, Bleeker et al8 examined the relationship between acute resynchronization and reverse remodeling in 100 patients with LV dyssynchrony of > 65 ms by tissue Doppler imaging. CRT immediately improved dyssynchrony in most subjects and remained identical after 6 months of CRT. Although there was a significant correlation between acute resynchronization and reverse remodeling, the strength of the relationship was low (r = 0.41).8
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Figure 4 Radial strain and strain rate changes after CRT in a representative responder. Before CRT, the early contracted segments reached early peak strains before the onset of ejection phase and opposite strain developed within the left ventricular wall during the ejection phase. Dyssynchrony and discoordination improved immediately after CRT as the early peak strains disappeared and were replaced by small and late systolic peak strains near the end of ejection phase.
Table 5 Recoordination/resynchronization and reverse remodeling Reduction in LV ESV (%) n = 30
Equation
Recoordination (%) RDI-B y = 0.5x + 21 RDI-M y = 0.45x +12 RDI-12 y = 0.56x +15 Resynchronization (%) AS-P delay y = 0.34x + 15 RS-SD y = 0.07x + 28 MD-6 y = 0.08x + 28
r
P
Increase in LV EF (%) Equation
r
P
0.42 .02 y = 0.21x + 10 0.47 .008 0.75 <.001 y = 0.19x + 7 0.81 <.001 0.62 <.001 y= 0.25x + 7 0.71 <.001 0.43 0.27 0.30
.02 .16 .10
y = 0.17x + 7 0.55 y = 0.03x + 12 0.30 y = 0.04 + 13 0.34
.002 .11 .07
RDI, Radial discoordination index; EF, ejection fraction; RDI-B, RDI derived from 6 basal LV segments; RDI-M, RDI derived from 6 midLV segments; RDI-12, RDI derived from 6 basal-LV and 6 mid-LV segments; AS-P delay, anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments; ESV, end-systolic volume.
Similar to their finding, we did observe a significant but weak correlation between acute resynchronization and reverse remodeling. The observation that recoordination is correlated with reverse remodeling supports the notion that reducing the opposing strain
rates leads to more efficient and coordinated contraction.10 Reversing the detrimental consequences of discoordinated contraction will decrease internal energy wasting, improve efficiency of myocardial contraction, coordinate papillary muscle contraction, and reduce mitral regurgitation, thereby allowing a decrease of LV dilatation in the long run.10,21,22 The acute recoordination is less directly applicable to the prediction of response before CRT implantation because patients must already be treated to reveal the recoordination effect.23 More valuable would be that response to CRT can be predicted on the basis of baseline discoordination. Our findings suggest a point of non-return that may limit the response to CRT. Three of 30 patients had a high value of baseline discoordination (RDI-M > 200%) and dyssynchrony. These patients did not respond to CRT, although one of them demonstrated a substantial reduction in RDI after CRT. In the 3 patients, left ventricles were markedly dilated and systolic thinning replaced systolic thickening in most of the segments. CRT may be too late to show benefits in such patients with severe LV dysfunction and extreme disarray of the LV muscular layers. Two cutoff thresholds for baseline RDI are needed to predict response to CRT. One is the lower cutoff value that identifies the reserve contractile capacity. The other is the higher cutoff value that defines a threshold of LV dysfunction beyond which recoordination is harder to satisfy. Furthermore, lack of any recoordination despite different LV lead positions and device programming would be a reason not to use CRT. If patients do not achieve acute recoordination, it seems unlikely that they will benefit from CRT. The computation of dyssynchrony and discoordination was performed automatically.24 The analyst only has to export the strain
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Figure 5 Receiver operating characteristics analysis to assess the ability of QRS duration, baseline dyssynchrony, baseline discoordination (A), acute resynchronization, and acute recoordination (B) to predict CRT responders. Acute recoordination provided the best separation for prediction of CRT responders compared with acute resynchronization, baseline dyssynchrony, or baseline discoordination. AUC, Area under curve; CI, confidence interval.
and strain rate data and manually enter the times of QRS onset, aortic valve opening, and aortic valve closure. Because of the high degree of automatization, evaluation of 1 patient can be performed in 5 to 10 minutes, a time that could be reduced further by the incorporation of the analysis into the echocardiography analysis software.
marking of ejection phase may add a source of potential error to the quantification of RDI. The effect of LV lead position, apical segments, or other candidates, such as longitudinal or circumferential strain on myocardial discoordination, was not investigated in this study and is a potentially important issue to explore further in the future.
LIMITATIONS CONCLUSIONS The calculation of RDI was based on displacement measures by speckle-tracking strain imaging and not by direct measurement of myocardial wall thickness as it changes during the ejection phase. In addition, the calculation of RDI requires measurements of the timings of aortic valve opening and closure to identify the ejection phase. However, these measurements were collected at different times with potentially different heart rates and loading conditions from which the LV images were acquired. Thus, the
LV recoordination after CRT is an acute response and correlated well with reverse remodeling. Patients who exhibit acute recoordination are likely to respond to CRT, whereas patients who have a low value of RDI at baseline or an insufficient decrease in RDI at the immediate follow-up usually do not respond to CRT. This indicates that acute recoordination is mandatory for response to CRT.
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Figure 6 Bland–Altman plots of intraobserver (A) and interobserver (B) variability of discoordination measures. RDI-B, RDI-M, and RDI-12 indicate the RDI measured from 6-basal, 6-mid, and 12 (ie, 6-basal and 6-mid) LV segments, respectively. Linear lines indicate mean difference of repeated measures; stippled lines indicate limits of agreement (62 standard deviation). Close agreement was observed when lesser degrees of discoordination were present (RDI < 50%).
REFERENCES 1. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350: 2140-50. 2. Hawkins NM, Petrie MC, MacDonald MR, Hogg KJ, McMurray JJ. Selecting patients for cardiac resynchronization therapy: electrical or mechanical dyssynchrony? Eur Heart J 2006;27:1270-81. 3. Yu CM, Fung JW, Zhang Q, Chan CK, Chan YS, Lin H, et al. Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation 2004; 110:66-73. 4. Suffoletto MS, Dohi K, Cannesson M, Saba S, Gorcsan J 3rd. Novel speckle-tracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation 2006;113:960-8. 5. Bax JJ, Bleeker GB, Marwick TH, Molhoek SG, Boersma E, Steendijk P, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004;44:1834-40. 6. Kleijn SA, van Dijk J, de Cock CC, Allaart CP, van Rossum AC, Kamp O. Assessment of intraventricular mechanical dyssynchrony and prediction of response to cardiac resynchronization therapy: comparison between tissue Doppler imaging and real-time three-dimensional echocardiography. J Am Soc Echocardiogr 2009;22:1047-54. 7. Seo Y, Ishizu T, Sakamaki F, Yamamoto M, Machino T, Yamasaki H, et al. Mechanical dyssynchrony assessed by speckle tracking imaging as a reliable predictor of acute and chronic response to cardiac resynchronization therapy. J Am Soc Echocardiogr 2009;22:839-46. 8. Bleeker GB, Mollema SA, Holman ER, Van de Veire N, Ypenburg C, Boersma E, et al. Left ventricular resynchronization is mandatory for response to cardiac resynchronization therapy: analysis in patients with
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echocardiographic evidence of left ventricular dyssynchrony at baseline. Circulation 2007;116:1440-8. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation 2008;117:2608-16. Kirn B, Jansen A, Bracke F, van Gelder B, Arts T, Prinzen FW. Mechanical discoordination rather than dyssynchrony predicts reverse remodeling upon cardiac resynchronization. Am J Physiol Heart Circ Physiol 2008; 295:H640-6. Barold SS, Ilercil A, Herweg B. Echocardiographic optimization of the atrioventricular and interventricular intervals during cardiac resynchronization. Europace 2008;10(Suppl 3). iii88–95. Gorcsan J 3rd. Role of echocardiography to determine candidacy for cardiac resynchronization therapy. Curr Opin Cardiol 2008;23:16-22. Tanaka H, Hara H, Saba S, Gorcsan J 3rd. Prediction of response to cardiac resynchronization therapy by speckle tracking echocardiography using different software approaches. J Am Soc Echocardiogr 2009;22:677-84. Delgado V, Ypenburg C, van Bommel RJ, Tops LF, Mollema SA, Marsan NA, et al. Assessment of left ventricular dyssynchrony by speckle tracking strain imaging comparison between longitudinal, circumferential, and radial strain in cardiac resynchronization therapy. J Am Coll Cardiol 2008;51:1944-52. Rademakers LM, de Boeck BW, Maessen JG, Prinzen FW. Development of strategies for guiding cardiac resynchronization therapy. Heart Fail Clin 2008;4:333-45. Fornwalt BK, Delfino JG, Sprague WW, Oshinski JN. It’s time for a paradigm shift in the quantitative evaluation of left ventricular dyssynchrony. J Am Soc Echocardiogr 2009;22:672-6. Delgado V, Ypenburg C, Zhang Q, Mollema SA, Fung JW, Schalij MJ, et al. Changes in global left ventricular function by multidirectional strain assessment in heart failure patients undergoing cardiac resynchronization therapy. J Am Soc Echocardiogr 2009;22:688-94.
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18. Kapetanakis S, Kearney MT, Siva A, Gall N, Cooklin M, Monaghan MJ. Real-time three-dimensional echocardiography: a novel technique to quantify global left ventricular mechanical dyssynchrony. Circulation 2005;112:992-1000. 19. Yu CM, Gorcsan J 3rd, Bleeker GB, Zhang Q, Schalij MJ, Suffoletto MS, et al. Usefulness of tissue Doppler velocity and strain dyssynchrony for predicting left ventricular reverse remodeling response after cardiac resynchronization therapy. Am J Cardiol 2007;100:1263-70. 20. Carasso S, Rakowski H, Witte KK, Smith P, Carasso D, Garceau P, et al. Left ventricular strain patterns in dilated cardiomyopathy predict response to cardiac resynchronization therapy: timing is not everything. J Am Soc Echocardiogr 2009;22:242-50.
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21. Prinzen FW, Van Oosterhout MF, Vanagt WY, Storm C, Reneman RS. Optimization of ventricular function by improving the activation sequence during ventricular pacing. Pacing Clin Electrophysiol 1998;21:2256-60. 22. Prinzen FW, Peschar M. Relation between the pacing induced sequence of activation and left ventricular pump function in animals. Pacing Clin Electrophysiol 2002;25:484-98. 23. Kass DA. Highlighting the R in CRT. Circulation 2007;116:1434-6. 24. Olsen NT, Mogelvang R, Jons C, Fritz-Hansen T, Sogaard P. Predicting response to cardiac resynchronization therapy with cross-correlation analysis of myocardial systolic acceleration: a new approach to echocardiographic dyssynchrony evaluation. J Am Soc Echocardiogr 2009;22: 657-64.
Background: Mechanical discoordination as studied by magnetic resonance imaging has been shown to be a better predictor of left ventricular (LV) reverse remodeling after cardiac resynchronization therapy (CRT) compared with mechanical dyssynchrony. Materials and Methods: This study assessed the value of acute recoordination derived from speckle-tracking echocardiography for predicting response to CRT compared with acute resynchronization. Thirty patients with heart failure scheduled for CRT were studied at baseline, immediately after CRT, and after 6 months of CRT. Acute recoordination after CRT was indexed by an acute reduction in radial discoordination index (RDI), defined as the ratio of average myocardial thinning to thickening during the ejection phase. Results: CRT responders were defined as those patients whose LV end-systolic volume decreased by $ 15% at the 6-month follow-up. Immediately after CRT, the responders (n = 18) demonstrated a significant reduction in RDI (P < .001), which was sustained at the 6-month follow-up (P < .001). The nonresponders, however, did not show a significant change in RDI after CRT. LV reverse remodeling at the 6-month follow-up was significantly correlated with acute recoordination (r = 0.75, P < .001) but weakly correlated with acute resynchronization (r = 0.43; P = .02). Conclusions: Receiver operating characteristic analysis revealed that acute recoordination provided the best separation for prediction of CRT responders compared with acute resynchronization, baseline dyssynchrony, or baseline discoordination. LV recoordination after CRT is an acute phenomenon and predicts response to CRT at 6-month follow-up better than resynchronization. (J Am Soc Echocardiogr 2010;23:611-20.) Keywords: Cardiac resynchronization therapy, Discoordination, Dyssynchrony, Echocardiography, Speckle tracking
Cardiac resynchronization therapy (CRT) has proven helpful in patients with heart failure and a wide QRS complex.1 Despite its efficacy, 30% to 40% of patients do not benefit from CRT.2 Several studies suggested that mechanical dyssynchrony is a potential tool to identify CRT responders.3-7 In addition, immediate reduction in left ventricular (LV) dyssynchrony after CRT was thought to predict LV reverse remodeling at 6-month follow-up.8 However, the Predictors of Response to CRT (PROSPECT) study showed disappointing results on the use of mechanical dyssynchrony in predicting response to CRT.9 From the First Division of Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan (C.L.W., C.T.W., Y.H.Y., L.S.W., C.J.C., W.J.H., L.A.H., C.T.K.); College of Medicine, Chang Gung University, Taoyuan, Taiwan (C.L.W., C.J.C., W.J.H., L.A.H., C.T.K.); and Department of Cardiology, RIPAS Hospital, Bander Seri Begawan, Brunei Darussalam (N.L.). Reprint requests: Chi-Tai Kuo, MD, First Division of Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, 5, Fushin Street, Kweishan Hsiang, Taoyuan, Taiwan (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2010 by the American Society of Echocardiography. doi:10.1016/j.echo.2010.03.012
In a recent study using circumferential strain by magnetic resonance imaging, Kirn et al10 demonstrated that mechanical discoordination (opposite strain within the LV wall) predicted reverse remodeling after CRT better than mechanical dyssynchrony. In the present study, we hypothesize that LV recoordination rather than resynchronization is a better approach to predict response to CRT. A novel approach to detect LV recoordination with speckletracking echocardiography was evaluated for predicting CRT response compared with resynchronization derived from classic dyssynchrony metrics. Immediate LV recoordination after CRT was indexed by an acute reduction in radial discoordination index (RDI), defined as the ratio of average myocardial thinning to thickening during the ejection phase.
MATERIALS AND METHODS Patients Consecutive patients with heart failure scheduled for CRT implantation were enrolled. The selection criteria for CRT included moderate to severe heart failure (New York Heart Association functional class III and IV) despite optimal medical therapy, LV ejection 611
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Abbreviations
AS-P delay = Time difference between the anteroseptal and posterior segments CRT = Cardiac resynchronization therapy EF = Ejection fraction LV = Left ventricular MD-6 = Time difference between the earliest and latest segments of 6 segments
PROSPECT = Predictors of Response to CRT study
RDI = Radial discoordination index RDI-B = 6 basal LV segments
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fraction (EF) # 35%, and QRS duration > 120 ms. Two agematched groups with narrow QRS (duration < 120 ms) served as controls: 1) patients without structural heart disease and with a normal echocardiogram (normal group) and 2) patients with LV EF < 35% (low EF group). Patients’ clinical status, LV volumes, and EF were assessed before CRT implantation and after 6 months of CRT. LV dyssynchrony and discoordination were assessed at baseline, immediately after CRT, and at a 6-month followup. Each parameter was measured from 3 consecutive beats and averaged for purpose of analysis.
Table 1 Clinical characteristics Narrow QRS control groups
Age (y) Female, n (%) Ischemic cause, n (%) LV EF (%) LV EDV (mL) QRS duration (ms)
Echocardiography Subjects were imaged in the left lateral decubitus position with a commercially available system (Vivid 7, General Electric Vingmed Ultrasound, Horten, Norway). Standard 2-dimensional and color Doppler data triggered to the QRS complex were saved in cineloop format. The LV volumes and EF were measured from the conventional apical 2- and 4-chamber images using the biplane Simpson method. The severity of mitral regurgitation was evaluated by color jet area and as percent jet area relative to left atrial size. Patients with a reduction of $ 15% in LV end-systolic volume at the 6-month follow-up were considered CRT responders. LV dyssynchrony and discoordination were evaluated by speckletracking echocardiography from the parasternal short-axis views at the level of papillary muscles and mitral valve. Gain settings and imaging width were adjusted to optimize the gray scale (frame rate of 50-80 hertz) and not to compromise the image resolution. Each time, we analyzed a single beat and the gating was set to begin with the onset of the QRS complex. End systole was chosen as the single frame for marking the region of interest to include the maximal wall thickness for strain analysis. The inner marker was traced to the endocardial-cavity interface at end systole, and the outer marker was traced to the LV epicardium to obtain reproducible time–strain curves.12,13 The software (EchoPac 6.1, General Electric Vingmed Ultrasound) automatically tracked the image speckle and produced 6 regional radial strain and strain rate curves. The region of interest
Low EF (n = 40)
CRT group (n = 30)
P
65 6 9 9 (45) 0 (0) 64 6 9 79 6 19 91 6 8
67 6 8 19 (48) 20 (50)* 26 6 6* 163 6 60* 95 6 11
69 6 10 18 (60) 12 (40)* 23 6 8* 172 6 65* 166 6 23*,†
.22 .48 .001 <.001 <.001 <.001
EF, Ejection fraction; CRT, cardiac resynchronization therapy; LV, left ventricular; EDV, end-diastolic volume. *P < .001 vs normal group. † P < .001 vs low EF group.
Table 2 Clinical characteristics at baseline and 6 months after cardiac resynchronization therapy Nonresponders (n = 12)
RDI-M = 6 mid-LV segments Cardiac Resynchronization RDI-12 = 12 LV segments Therapy Procedure RS-SD = Standard deviation The pacing leads were posiof times to peak strain for 6 tioned at the right ventricular segments apex or mid-septum, at the right atrial appendage, and in the posterior or posterolateral branch of coronary vein. The atrioventricular interval was optimized using the established method to ensure adequate LV filling.11 No adjustments were made to the interventricular interval before the 6-month follow-up. The local ethics committee approved the study protocol, and all subjects gave informed consent.
Normal (n = 20)
Age (y) Female, n (%) Ischemic cause, n (%) QRS duration (ms) Medication, n (%) ACE inhibitors/ARB B-blockers Diuretics NYHA class Baseline 6 months LV EDV (mL) Baseline 6 months LV ESV (mL) Baseline 6 months LV EF (%) Baseline 6 months Mitral regurgitation (%) Baseline 6 months
67 6 11 6 (50) 8 (67) 170 6 29
Responders (n = 18)
P
71 6 8 12 (67) 4 (22) 164 6 20
.24 .36 .02 .47
17 (94) 16 (89) 12 (57)
1.0 1.0 .70
3.2 6 0.3 2.6 6 0.7†
3.1 6 0.3 1.5 6 0.5*
.65 <.001
194 6 75 209 6 90
158 6 55 101 6 33*
.14 .002
156 6 72 171 6 83
121 6 48 56 6 24*
.12 .001
21 6 8 21 6 8
24 6 7 46 6 8*
.37 <.001
22 6 10 20 6 10
24 6 12 8 6 5*
.68 .003
11 (92) 10 (83) 9 (75)
ACE, Angiotensin-converting enzyme; ARB, angiotensin receptor blockers; NYHA, New York Heart Association; LV, left ventricular; EDV, end-diastolic volume; ESV, end-systolic volume; EF, ejection fraction. Values are mean 6 standard deviation or number (percentage). *P < .001 vs baseline. † P = .008 vs baseline.
was redrawn if tracking quality was poor or the curves were viewed to be inadequate. Radial Dyssynchrony and Discoordination Analysis The data of radial strain and strain rate were exported to a spreadsheet program (Microsoft Excel, Microsoft Corp, Seattle, WA) to calculate dyssynchrony and discoordination. The time to peak strain
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Table 3 Discoordination and dyssynchrony measurements in control groups and cardiac resynchronization therapy group Narrow QRS control groups
RDI-B RDI-M RDI-12 AS-P delay RS-SD MD-6
CRT group
Normal (n = 20)
Low EF (n= 40)
All CRT patients (n = 30)
Nonresponders (n = 12)
Responders (n = 18)
1 (0, 2)* 1 (0, 1)* 1 (0, 1)* 53 (28, 78)* 28 (20, 39)* 62 (48, 85)*
11 (6, 19)† 18 (10, 30)* 15 (8, 22)* 118 (75, 180)* 90 (58, 129)* 227 (125, 310)*
16 (7, 59) 58 (37, 115) 30 (15, 69) 305 (189, 353) 175 (131, 198) 371 (306, 470)
17 (9, 38) 36 (10, 163) 18 (11, 58) 192 (110, 318) 120 (78, 181) 292 (191, 435)
14 (2, 62) 70 (51, 115)‡ 32 (18, 78) 326 (193, 354)‡ 174 (130, 202)‡ 365 (305, 466)
RDI, Radial discoordination index; EF, ejection fraction; RDI-B, RDI derived from 6 basal LV segments; RDI-M, RDI derived from 6 mid-LV segments; RDI-12, RDI derived from 6 basal-LV and 6 mid-LV segments; AS-P delay, anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments. Values are median (first, third quartiles). *P < .001 vs all CRT patients. † P < .05 vs all CRT patients. ‡ P < .05 vs baseline nonresponders.
from each of the 6 mid-LV segments was measured. Dyssynchrony indices were defined as the time difference between the anteroseptal and posterior segments (AS-P delay), the standard deviation of times to peak strain for 6 segments (RS-SD), and the time difference between the earliest and the latest segments of the 6 segments (MD-6).4,14 The immediate resynchronization was defined as the percentage difference between preimplantation LV dyssynchrony and the one at immediate follow-up.8 The radial strain rate signals from the 6 segments were split into positive signals ep(t) and negative signals en(t). Averaging ep(t) and en(t) over 6 basal-LV or mid-LV signals resulted in average myocardial thickening and thinning, respectively. Integration of these signals in the ejection phase resulted in a positive strain ep, representing the amount of myocardial contraction, and a negative strain en, representing the amount of myocardial thinning. The timing of ejection phase (between aortic valve opening and aortic valve closure) was determined from the Doppler velocity signal at the LV outflow tract. RDI was calculated as a ratio of the amount of average myocardial thinning relative to the amount of average myocardial thickening (denominator) during the ejection phase.10 The RDI was measured from 6 basal LV segments (RDI-B), 6 mid-LV segments (RDI-M), and 12 (ie, 6 basal and 6 mid) LV segments (RDI-12). The difference between the preimplantation RDI and the RDI at immediate follow-up defined the acute recoordination. Statistical Analysis Data were expressed as mean 6 standard deviation for continuous variables and as absolute frequencies and relative percentages for categoric variables. Continuous variables were compared by means of 1-way analysis of variance for overall comparison and the Dunnett test for post hoc comparisons. The chi-square test with the Fisher exact test (if necessary) was used to compare categoric variables. Dyssynchrony and discoordination indices were summarized with the median and 25th and 75th percentiles and compared with the Mann–Whitney test for each pair of groups. Changes over time within a group were analyzed by the Friedman test and Wilcoxon test for post hoc comparisons. The Pearson correlation analysis was performed to determine the relationship between acute recoordination/resynchronization and reverse remodeling at the 6-month follow-up. Receiver operating characteristic analysis was used to determine the optimal cutoff value of the variables for prediction of re-
sponse to CRT.13 Reproducibility was tested using the Bland–Altman method. For all tests, a value of P < .05 was considered statistically significant.
RESULTS Baseline variables of the studied patients are summarized in Tables 1 and 2. All patients who received CRT survived during the 6-month follow-up. Nonresponders were similar to responders in all aspects, except for greater prevalence of ischemic cardiomyopathy. Both groups improved clinically, as indicated by the decrease in New York Heart Association class. However, after 6 months of CRT the LV volumes and mitral regurgitation decreased and LV EF increased in the responders only. Comparisons of Baseline Dyssynchrony and Discoordination Comparisons of dyssynchrony and discoordination indices among control and CRT groups are shown in Table 3. All indices differed significantly between control and CRT groups. Significant differences were present between nonresponders and responders in baseline RDI-M, AS-P delay, and RS-SD. Figures 1 and 2 show baseline dyssynchrony and discoordination analyses in a normal subject, a nonresponder, and a responder. In the normal subject, all midventricular segments contracted synchronously and the peak strain of each segment occurred almost simultaneously after the end of ejection phase (Figure 1). During the ejection phase, myocardial thickening was dominant and myocardial thinning was negligible. In the responder, peak radial strain occurred before the ejection phase in 3 early contracted segments (Figure 2). These early contracted segments developed myocardial thinning that was indicated by the negative strain rate during the ejection phase. Similarly, the strain analysis in the nonresponder showed a comparable measure of dyssynchrony by calculating the time-to-peak difference between the early and late contracted segments. However, in the nonresponder, the early peak strain occurred later at the early ejection phase with a smaller peak value and in fewer segments compared with the responder. Therefore, the amount of myocardial thinning relative to myocardial thickening during the ejection phase was smaller than that of the responder.
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show a significant change after CRT. In contrast, all indices differed significantly after CRT in the responders. In the post hoc comparisons, all indices demonstrated a significant reduction immediately after CRT. At the 6-month follow-up, the reductions in RDI and all dyssynchrony indices by CRT were still present. Figure 3 presents the individual values of RDI-M and AS-P delay before and after CRT. The baseline RDI-M values of the responders and nonresponders were widely separated. The responders had a medium to high value (35%-160%) that consistently decreased immediately after CRT (P < .001). In contrast, the nonresponders had a low (<40%) or high RDI-M (>200%) value that increased or did not decrease sufficiently at the immediate follow-up (Figure 3A). The values of AS-P delay showed substantial reductions immediately after CRT in most of the responders but also in some of the nonresponders (Figure 3B). Figure 4 shows representative strain and strain rate changes in a responder. In the responders, the early contracted segments, usually anteroseptal and inferoseptal walls, reached early peak strains before the onset of ejection phase. These early contracted segments developed positive strain rates before the ejection phase and mostly negative strain rates during the ejection phase. Immediately after CRT, the early peak strains disappeared and were replaced by small and late systolic peak strains near the end of ejection phase. As a result, the myocardial thinning of the early contracted segments diminished and RDI-M reduced immediately after CRT. The AS-P delay also decreased because of the disappearance of the early peak strain. After 6 months of CRT, LV function and discoordination improved as indicated by the increased peak strains in all segments and a reduced value of RDI-M. Table 5 shows the relationships between acute recoordination/resynchronization and reverse remodeling. LV reverse remodeling was significantly correlated with acute recoordination (RDI-M, r = 0.75, P < .001) but weakly correlated with acute resynchronization (AS-P delay, r = 0.43, P = .02). Receiver operating characteristic analysis (Figure 5) revealed that acute recoordination provided the best separation for prediction of CRT responders compared with acute resynchronization, baseline dyssynchrony, or baseline discoordination (acute RDI-M reduction > 20%: sensitivity 100%, specificity 91%; acute RDI-12 reduction > 10%: sensitivity 94%, specificity 100%). RDI-M was the only baseline index that was useful for prediction of responders (area under curve 0.73, cutoff value of the baseline RDI-M > 40%; sensitivity 94%, specificity 67%). Figure 1 Dyssynchrony indices and RDI-M in a normal control. Tracings of strain and strain rate of 6 mid-ventricular segments are represented as colored lines. The time course of the average thickening [ep(t)] and average thinning [en(t)] are represented as a solid black line and a dashed black line, respectively. The amount of myocardial thickening (ep) and thinning (en) during the ejection phase are represented with the area below curve ep(t) and above curve en(t) (zero in this subject), respectively. RDI-M was calculated as -(en/ep)100%. During the ejection phase, the amount of average myocardial thickening was dominant and the amount of average myocardial thinning was negligible. AS-P delay, Anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments.
Recoordination and Resynchronization after Cardiac Resynchronization Therapy Table 4 shows index changes over time after CRT. In the nonresponders, all discoordination and dyssynchrony indices failed to
Subgroup Analysis for Ischemic Cause Patients with ischemic cardiomyopathy have lower baseline discoordination than patients with nonischemic dilated cardiomyopathy (median RDI-M, 38% vs 72%, P = .02; median RDI-12, 17% vs 38%, P = .05). In patients with ischemic cardiomyopathy, acute recoordination provided the best separation for prediction of response compared with acute resynchronization, baseline dyssynchrony, and baseline discoordination (acute RDI-M reduction > 20%: area under the curve 0.91, sensitivity 100%, specificity 87%; acute RDI-12 reduction > 8%: area under the curve 0.91, sensitivity 100%, specificity 87%). Reproducibility Reproducibility was tested in a random selection of 20 patients with CRT at baseline and immediate follow-up. The interobserver and intraobserver variability of RDI were 9% 6 11% and 7% 6 12% for RDI-B, 11% 6 12% and 10 6 11% for RDI-M, and 10% 6 16% and 7% 6 10% for RDI-12, respectively. Variability of RDI seemed to be related to degree of discoordination in individual patients
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Figure 2 Baseline dyssynchrony indices and RDI-M in a nonresponder and responder. Despite a comparable measure of dyssynchrony, discoordination analysis reveals a smaller amount of RDI-M in the nonresponder compared with the responder. AS-P delay, Anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments. (Figure 6). Close agreement was observed when lesser degrees of discoordination were present (RDI < 50%). However, variability of RDI increased as the degree of radial discoordination increased, in particular RDI > 100%. Limits of agreement on Bland–Altman analysis ranged from 24% to 33%.
DISCUSSION This study shows that RDI, an index of mechanical discoordination, performs better than indices of mechanical dyssynchrony in discriminating responders and nonresponders, and in detecting a substantial
immediate decline mostly in responders. Acute recoordination correlates better with reverse remodeling after 6 months of CRT than acute resynchronization. These findings support the notion that mechanical discoordination reflects the reserve contractile capacity that can be recruited by CRT and is a key target for long-term CRT benefits.10 A comprehensive assessment of abnormal LV mechanics caused by asynchronous activation can be quantified by means of internal stretch fraction or RDI.10 In left bundle branch block, the septal wall is activated early, whereas the lateral and posterior walls are activated late.15 The asynchronous activation leads to early septal and late posterior–lateral contraction. Early septal contraction causes posterior–lateral thinning or stretching, followed by late posterior–lateral contraction
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Table 4 Changes of discoordination and dyssynchrony indices after cardiac resynchronization therapy Nonresponders (n = 12)
RDI-B (%) RDI-M (%) RDI-12 (%) AS-P delay (ms) RS-SD (ms) MD-6 (ms)
Responders (n = 18)
Baseline
Immediate
6 mo
P
Baseline
Immediate
6 mo
P
17 (9, 38) 36 (10, 163) 18 (11, 58) 192 (110, 318) 120 (78, 181) 292 (191, 435)
18 (2, 71) 58 (31, 125) 33 (10, 75) 124 (78, 299) 108 (80, 173) 218 (167, 379)
11 (4, 37) 54 (29, 218) 35 (11, 49) 157 (77, 393) 107 (92, 218) 258 (223, 440)
.08 .21 .78 .17 .78 .47
14 (2, 62) 70 (51, 115) 32 (18, 78) 326 (193, 354) 174 (130, 202) 365 (305, 466)
5 (2, 7)* 10 (3, 17)* 7 (4, 11)* 109 (69, 188)* 71 (50, 146)* 152 (114, 321)*
3 (1, 4)*,‡ 2 (1, 4)*,† 3 (1, 4)*,† 76 (14, 111)*,† 50 (11, 75)*,† 117 (28, 162)*,†
.001 <.001 <.001 <.001 <.001 <.001
RDI, Radial discoordination index; EF, ejection fraction; RDI-B, RDI derived from 6 basal LV segments; RDI-M, RDI derived from 6 mid-LV segments; RDI-12, RDI derived from 6 basal-LV and 6 mid-LV segments; AS-P delay, anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments. *P < .01 vs baseline. † P < .01 versus immediate. ‡ P < .05 versus immediate.
Figure 3 Changes of RDI-M (A) and AS-P delay (B) after CRT in responders and nonresponders. Responders had a medium to high value of RDI-M, which consistently reduced after CRT. Mechanical dyssynchrony reduced significantly after CRT in the responders but also in some of the nonresponders. AS-P delay, Anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments.
causing septal thinning or stretching. The internal stretch or thinning leads to energy wasting and a decline in efficiency of myocardial contraction.10,16 CRT can reverse the adverse mechanical consequences by synchronizing LV activation and contraction. Patients who exhibit acute recoordination will respond to CRT, whereas patients who have a low level of baseline discoordination or an insufficient improvement in discoordination usually do not respond to CRT. Our results are consistent with a prior study that showed an index of mechanical discoordination (opposite strain within the LV wall) was superior to indices of mechanical dyssynchrony at predicting response to CRT.10 Mechanical dyssynchrony refers simply to the timing of peak or onset of contraction. Kirn et al10 used circumferential strain from magnetic resonance imaging to quantify baseline discoordination and mechanical dyssynchrony in 160 sites, covering 70% of the LV wall. Our findings suggest that baseline discoordination by measuring only mid-LV radial strain rate was useful for predicting response to CRT. RDI-M showed an almost equivalent ability with RDI-12 in identifying CRTresponders. Adding basal-LV segments into the analysis may yield more comprehensive LV functional assessment but did not improve the ability of prediction of CRT responders. Evaluation of LV dyssynchrony and discoordination using speckletracking analysis is feasible in all 3 deformation types: radial, circumferential, and longitudinal strain.17 Using radial strain to assess dyssynchrony or discoordination is sensible because the ratio of thinning to thickening is usually high, indicating a better signal to noise ratio compared with longitudinal and circumferential strain. In addition, Delgado et al14 showed that among the 3 deformation types, only baseline dyssynchrony assessed with radial strain (both AS-P delay and RSSD) was able to identify potential CRT responders. This pilot study found that discoordination assessed with radial strain rate was useful for identifying CRT responders. Further study is needed to establish the feasibility and value of applying speckle-tracking analysis of recoordination with longitudinal and circumferential strain.17 Previous studies have reported the effect of CRT on LV dyssynchrony,5,8,18-20 most of which showed immediate reduction in dyssynchrony after CRT.5,8,18 For instance, Bleeker et al8 examined the relationship between acute resynchronization and reverse remodeling in 100 patients with LV dyssynchrony of > 65 ms by tissue Doppler imaging. CRT immediately improved dyssynchrony in most subjects and remained identical after 6 months of CRT. Although there was a significant correlation between acute resynchronization and reverse remodeling, the strength of the relationship was low (r = 0.41).8
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Figure 4 Radial strain and strain rate changes after CRT in a representative responder. Before CRT, the early contracted segments reached early peak strains before the onset of ejection phase and opposite strain developed within the left ventricular wall during the ejection phase. Dyssynchrony and discoordination improved immediately after CRT as the early peak strains disappeared and were replaced by small and late systolic peak strains near the end of ejection phase.
Table 5 Recoordination/resynchronization and reverse remodeling Reduction in LV ESV (%) n = 30
Equation
Recoordination (%) RDI-B y = 0.5x + 21 RDI-M y = 0.45x +12 RDI-12 y = 0.56x +15 Resynchronization (%) AS-P delay y = 0.34x + 15 RS-SD y = 0.07x + 28 MD-6 y = 0.08x + 28
r
P
Increase in LV EF (%) Equation
r
P
0.42 .02 y = 0.21x + 10 0.47 .008 0.75 <.001 y = 0.19x + 7 0.81 <.001 0.62 <.001 y= 0.25x + 7 0.71 <.001 0.43 0.27 0.30
.02 .16 .10
y = 0.17x + 7 0.55 y = 0.03x + 12 0.30 y = 0.04 + 13 0.34
.002 .11 .07
RDI, Radial discoordination index; EF, ejection fraction; RDI-B, RDI derived from 6 basal LV segments; RDI-M, RDI derived from 6 midLV segments; RDI-12, RDI derived from 6 basal-LV and 6 mid-LV segments; AS-P delay, anteroseptal-posterior delay; RS-SD, standard deviation in times to peak strain of 6 radial segments; MD-6, maximal difference in times to peak strain of 6 radial segments; ESV, end-systolic volume.
Similar to their finding, we did observe a significant but weak correlation between acute resynchronization and reverse remodeling. The observation that recoordination is correlated with reverse remodeling supports the notion that reducing the opposing strain
rates leads to more efficient and coordinated contraction.10 Reversing the detrimental consequences of discoordinated contraction will decrease internal energy wasting, improve efficiency of myocardial contraction, coordinate papillary muscle contraction, and reduce mitral regurgitation, thereby allowing a decrease of LV dilatation in the long run.10,21,22 The acute recoordination is less directly applicable to the prediction of response before CRT implantation because patients must already be treated to reveal the recoordination effect.23 More valuable would be that response to CRT can be predicted on the basis of baseline discoordination. Our findings suggest a point of non-return that may limit the response to CRT. Three of 30 patients had a high value of baseline discoordination (RDI-M > 200%) and dyssynchrony. These patients did not respond to CRT, although one of them demonstrated a substantial reduction in RDI after CRT. In the 3 patients, left ventricles were markedly dilated and systolic thinning replaced systolic thickening in most of the segments. CRT may be too late to show benefits in such patients with severe LV dysfunction and extreme disarray of the LV muscular layers. Two cutoff thresholds for baseline RDI are needed to predict response to CRT. One is the lower cutoff value that identifies the reserve contractile capacity. The other is the higher cutoff value that defines a threshold of LV dysfunction beyond which recoordination is harder to satisfy. Furthermore, lack of any recoordination despite different LV lead positions and device programming would be a reason not to use CRT. If patients do not achieve acute recoordination, it seems unlikely that they will benefit from CRT. The computation of dyssynchrony and discoordination was performed automatically.24 The analyst only has to export the strain
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Figure 5 Receiver operating characteristics analysis to assess the ability of QRS duration, baseline dyssynchrony, baseline discoordination (A), acute resynchronization, and acute recoordination (B) to predict CRT responders. Acute recoordination provided the best separation for prediction of CRT responders compared with acute resynchronization, baseline dyssynchrony, or baseline discoordination. AUC, Area under curve; CI, confidence interval.
and strain rate data and manually enter the times of QRS onset, aortic valve opening, and aortic valve closure. Because of the high degree of automatization, evaluation of 1 patient can be performed in 5 to 10 minutes, a time that could be reduced further by the incorporation of the analysis into the echocardiography analysis software.
marking of ejection phase may add a source of potential error to the quantification of RDI. The effect of LV lead position, apical segments, or other candidates, such as longitudinal or circumferential strain on myocardial discoordination, was not investigated in this study and is a potentially important issue to explore further in the future.
LIMITATIONS CONCLUSIONS The calculation of RDI was based on displacement measures by speckle-tracking strain imaging and not by direct measurement of myocardial wall thickness as it changes during the ejection phase. In addition, the calculation of RDI requires measurements of the timings of aortic valve opening and closure to identify the ejection phase. However, these measurements were collected at different times with potentially different heart rates and loading conditions from which the LV images were acquired. Thus, the
LV recoordination after CRT is an acute response and correlated well with reverse remodeling. Patients who exhibit acute recoordination are likely to respond to CRT, whereas patients who have a low value of RDI at baseline or an insufficient decrease in RDI at the immediate follow-up usually do not respond to CRT. This indicates that acute recoordination is mandatory for response to CRT.
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Figure 6 Bland–Altman plots of intraobserver (A) and interobserver (B) variability of discoordination measures. RDI-B, RDI-M, and RDI-12 indicate the RDI measured from 6-basal, 6-mid, and 12 (ie, 6-basal and 6-mid) LV segments, respectively. Linear lines indicate mean difference of repeated measures; stippled lines indicate limits of agreement (62 standard deviation). Close agreement was observed when lesser degrees of discoordination were present (RDI < 50%).
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