Background
The mechanisms of improvement of left ventricular (LV) function with cardiac resynchronization therapy (CRT) are not yet elucidated. The aim of this study was to describe a new tool based on automatic quantification of the integrals of regional longitudinal strain signals and evaluate changes in LV strain distribution after CRT.
Methods
This was a retrospective observational study of 130 patients with heart failure before CRT device implantation and after 3 to 6 months of follow-up. Integrals of regional longitudinal strain signals (from the beginning of the cardiac cycle to strain peak [ I L,peak ] and to the instant of aortic valve closure [ I L,avc ]) were analyzed retrospectively with custom-made algorithms. Response to CRT was defined as a decrease in LV end-systolic volume of ≥15%.
Results
Responders (61%) and nonresponders (39%) showed similar baseline values of regional I L,peak and I L,avc . At follow-up, significant improvements of midlateral I L,peak and of midlateral I L,avc were noted only in responders. Midlateral I L,avc showed a relative increase of 151 ± 276% in responders, whereas a decrease of 33 ± 69% was observed in nonresponders. The difference between I L,avc and I L,peak (representing wasted energy of the LV myocardium) of the lateral wall showed a relative change of −59 ± 103% in responders between baseline and CRT, whereas in nonresponders, the relative change was 21 ± 113% ( P = .009).
Conclusions
Strain integrals revealed changes between baseline and CRT in the lateral wall, demonstrating the beneficial effects of CRT on LV mechanics with favorable myocardial reverse remodeling.
Assessment of left ventricular (LV) mechanical dyssynchrony in patients with heart failure is typically based on the echocardiographic analysis of differences in timing of myocardial velocity or deformation. However, no echocardiographic parameter based on timing has so far been shown to be reliable enough to identify responders to cardiac resynchronization therapy (CRT). Indeed, up to one third of patients with heart failure selected with respect to the very frequently reviewed guidelines in Europe and America do not improve clinically after implantation of CRT devices, and about 50% exhibit no LV reverse remodeling. Although there is strong evidence that CRT is beneficial overall, large studies involving echocardiographic evaluation of mechanical dyssynchrony have all shown negative results. There are, however, reasons to believe that there is still room for an assessment of mechanical dyssynchrony. Recent studies have focused less on the estimation of mechanical dyssynchrony and more on the characterization of the myocardial substrate to describe the complexity of LV mechanics before and during CRT. The development of speckle-tracking echocardiography, combining the assessment of LV dyssynchrony and contractility, was a cornerstone in this approach. This has been reinforced by reports that speckle-tracking is one of the most reliable tools for the assessment of myocardial regional and global function, particularly through the analysis of longitudinal strain. Observational studies have shown that longitudinal strain analysis reflects the segmental heterogeneity of myocardial function and that the increase in global longitudinal strain correlates with the degree of LV remodeling. However, this approach is often based on manually detected peaks, which could be a challenge in patients with severely altered LV function.
Most of the strain analysis methods proposed in the literature are based on peak timings and peak values of strain signals. Lim et al . published very promising results derived from algorithms based on longitudinal peaks and the relation between peaks and end-systolic values. These methods neglect the dynamics of strain signals, because the same values of strain peaks or timings can be observed with different strain curve morphologies. We hypothesized that a new approach based on the automatic quantification of the integrals of regional longitudinal strain signals, which takes into account the accumulated strain during different parts of the cardiac cycle (signal morphology), should be useful to evaluate LV mechanics both before and after CRT. The strain curves have thus been analyzed on the basis of the peaks, the delays, and the integrals. We proposed testing these automatic measurements of longitudinal strain curves to describe regional strain redistribution after CRT. Thus, the purpose of this study was twofold: (1) to demonstrate changes in patterns of strain signal at baseline and after CRT and (2) to determine whether they differ between CRT responders and nonresponders.
Methods
Study Population
One hundred forty-two patients with heart failure referred to Rennes University Hospital (Rennes, France) between 2010 and 2012 for implantation of CRT devices were retrospectively studied. Because of poor echogenicity, nine patients were excluded at the outset of the study. Three patients were lost to follow-up. We therefore studied 130 consecutive patients with heart failure. The etiology of dilated cardiomyopathy was both ischemic (38%) and nonischemic (62%). Coronary angiography was routinely performed to assess coronary artery disease. The etiology was considered ischemic either if patients had histories of myocardial infarction or revascularization or if they showed angiographic evidence of multiple-vessel or single-vessel disease along with left main or proximal left anterior coronary artery damage. The New York Heart Association (NYHA) class considered was the maximum functional class reached. At the time of inclusion, all patients were receiving stable optimized medical therapy.
This study was performed in accordance with the principles outlined in the Declaration of Helsinki on research in human subjects and with the procedures of the Rennes University Hospital Medical Ethics Committee (usual care).
The study was approved by a national review committee (CNIL 0507317b). Patients gave their informed consent.
Two-Dimensional Echocardiography
Complete baseline echocardiography (System 7; GE Vingmed Ultrasound AS, Horten, Norway), including standard grayscale (frame rate ≥ 50 Hz) and color Doppler tissue imaging (frame rate > 100 Hz) in the apical views (two-, three-, and four-chamber views), was performed before CRT device implantation and then 6 months after device implantation. Two-dimensional echocardiographic, Doppler, and DTI parameters were measured according to the guidelines of the American Society of Echocardiography. All measurements were averaged for three cardiac cycles. LV volumes and LV ejection fraction (LVEF) were calculated using the biplane modified Simpson method. Systolic ejection time was measured by recording aortic flow with pulsed-wave Doppler imaging. It was defined as the time between the onset of the QRS complex and aortic valve closure. A decrease in LV end-systolic volume of ≥15% of the baseline value, as measured by echocardiography 6 months after device implantation, was used to define a CRT responder.
Longitudinal Strain Signal Analysis
Offline analysis was performed using a previously validated software pack (BT12-EchoPAC PC; GE Healthcare, Milwaukee, WI). If five of six segments were reliably tracked and approved for speckle-tracking analysis, the images were accepted. Inadequately tracked segments were excluded from the analysis. Close attention was paid to the placement of timing markers. The first timing marker was placed at the onset of the QRS complex, and aortic valve closure was marked with the ejection time measured as previously described ( Figure 1 ).
Excel files (Microsoft Corporation, Redmond, WA) of apical four-chamber longitudinal strain analysis were exported for a dedicated analysis performed with MATLAB (The MathWorks Inc, Natick, MA). Using custom-made methods and algorithms, we analyzed the accumulated strain for each of the six available cardiac segments, through the calculation of the integral of each strain curve, during two different time intervals: first, from the beginning of the cardiac cycle (QRS onset) to the instant of the corresponding longitudinal strain peak ( I L,peak ) and second, to the instant of aortic valve closure ( I L,avc ) ( Figure 2 ). All values > −5% were considered noise and were thus not taken into consideration in calculating the integral.
We tested a number of integral-based indicators of regional longitudinal strain signals, all of them calculated automatically: classical parameters such as peak strain (amplitude), mean peak strain, and the SD of time to peak strain (SD t,peak ) and the novel parameters I L,avc and I L,peak for each segment, mean I L,avc and mean I L,peak , and finally the SD of I L,avc and the SD of I L, peak , corresponding to the energy dispersion for all six segments. DiffInt was calculated as the difference between I L,avc and I L,peak for a given segment. DiffInt might be considered an indicator of the wasted energy developed by the ventricle after the closure of the aortic valve.
Cardiac Resynchronization Therapy Device Implantation
Indications for CRT device implantation were based on the 2010 focused update of the European Society of Cardiology guidelines for devices used in heart failure therapy (patients in NYHA functional class III or ambulatory class IV, LVEF ≤ 35%, and QRS duration ≥ 120 msec or, alternatively, patients in NYHA class II, LVEF ≤ 35%, and QRS duration ≥ 150 msec). Each patient was implanted during the month after echocardiography. When required, patients received implantable cardiac defibrillators. Devices were implanted through a single left pectoral incision with transvenous LV lead insertion into a coronary sinus vein. The placement of the LV lead was lateral for 81 patients (62%), posterolateral or posterior for 18 patients (14%), and elsewhere for 31 patients (24%). The right ventricular lead was placed at the apex for 30 patients (23%) and in the interventricular septum for 100 patients (77%) and was not precisely determined for 31 patients (24%).
Statistical Analysis
Quantitative data are expressed as mean ± SD and qualitative data as numbers and percentages. Student t tests were used to compare means between independent samples, while paired Student t tests were used for intragroup comparisons. Dichotomized comparisons were assessed using χ 2 tests or Fisher exact tests.
Reproducibility was assessed in 10 randomly selected patients on the basis of traces obtained twice by the same observer and one time by a second observer. Intraclass correlation coefficients (ICCs) were calculated to assess the intraobserver and interobserver reproducibility of I L,avc and I L,peak . The level of statistical significance was set at P < .05.
Results
Study Population
One hundred thirty patients, with a mean age of 65 ± 9 years, of whom 73% were men (95 of 130), were analyzed retrospectively. One hundred seven (82%) were in NYHA functional class III. All patients were on stable, maximally tolerated heart failure medications according to the European Society of Cardiology guidelines. The mean LVEF was 27 ± 6%, and the mean QRS duration was 162 ± 23 msec. Heart rate did not differ between baseline and 6-month follow-up (67 ± 14 vs 65 ± 11 beats/min, P = .06). Follow-up was carried out for all patients at 6.6 ± 2.7 months. Eighty patients (62%) were responders at 6-month follow-up, with a mean LV end-systolic volume reduction of 42 ± 17%. Fifty patients (38%) were classified as nonresponders, with a mean LV end-systolic volume increase of 2 ± 14%. Baseline clinical and echocardiographic characteristics of responders versus nonresponders are summarized in Table 1 . There were no differences in baseline characteristics between responders and nonresponders, except for better response among male patients, those with nonischemic etiology of heart failure, and those with left bundle branch block.
| Variable | CRT responders ( n = 80) | CRT nonresponders ( n = 50) | P |
|---|---|---|---|
| Age (y) | 64.7 ± 9.7 | 65.5 ± 8.8 | .62 |
| Male | 53 (66%) | 42 (84%) | .04 |
| NYHA functional class II/III/IV | 14/66/0 | 9/41/0 | 1.00 |
| Ischemic etiology | 21 (26%) | 28 (56%) | <.001 |
| Heart rate (beats/min) | 69 ± 13 | 65 ± 14 | .14 |
| Sinus rhythm | 71 (89%) | 47 (94%) | .37 |
| QRS duration (msec) | 162 ± 21 | 163 ± 26 | .75 |
| LBBB morphology | 66 (82%) | 26 (52%) | <.001 |
| Drugs | |||
| ACE inhibitors or ARBs | 74 (92%) | 48 (96%) | .71 |
| β-blockers | 74 (92%) | 47 (94%) | 1.00 |
| Diuretics | 72 (90%) | 44 (88%) | .77 |
| Mitral regurgitation grade III or IV | 5 (6%) | 8 (16%) | .10 |
| LV ejection fraction (%) | 27 ± 6 | 28 ± 6 | .23 |
| LV end-diastolic diameter index (mm/m 2 ) | 36 ± 4 | 37 ± 5 | .39 |
| LV end-diastolic volume (mL) | 227 ± 63 | 234 ± 76 | .57 |
| LV end-systolic volume (mL) | 168 ± 55 | 169 ± 65 | .93 |
Reproducibility
Mean intraobserver and interobserver ICCs were, respectively, 0.90 and 0.90 for regional I L,avc and 0.84 and 0.87 for regional I L,peak . The minimal intraobserver ICC was 0.83 for regional basal septal I L,avc and 0.78 for regional midseptal I L,peak . The maximal intraobserver ICC was 0.96 for regional apical septal and lateral I L,avc and 0.99 for regional apical septal I L,peak . The minimal interobserver ICC was 0.80 for regional apical lateral I L,avc and 0.76 for regional midseptal I L,peak . The maximal interobserver ICC was 0.97 for regional midlateral I L,avc and 0.98 for regional basal septal I L,peak .
Patterns of Myocardial Strain Signal at Baseline Evaluation
In both responders and nonresponders, mean I L,avc ( P < .0001) was lower than mean I L,peak ( P < .0001), indicating that most of the segments reached their maximal deformation after aortic valve closure ( Table 2 ). Baseline global integral values were comparable between responders and nonresponders. The SD of I L, peak of all segments differed significantly at baseline between responders and nonresponders (1.15 ± 0.57% · sec −1 vs 0.99 ± 0.48% · sec −1 , respectively, P = .02). There was no regional difference in I L,peak at baseline evaluation between responders and nonresponders ( Figure 3 ). Segmental strain distribution between the septal and lateral walls during systole was heterogeneous: the mean of septal I L,avc (basal, middle, and apical septal segments) was significantly greater than the mean of lateral I L,avc (basal, middle, and apical lateral segments) in responders (1.32 ± 0.87% · sec −1 vs 1.01 ± 0.67% · sec −1 , P = .03) and in non-responders (1.38 ± 0.81% · sec −1 vs 0.89 ± 0.60% · s −1 , P = .003) ( Figure 4 ). This heterogeneity was comparable between responders and nonresponders.
| Variable | Responders | Nonresponders | ||||
|---|---|---|---|---|---|---|
| Baseline | CRT | P | Baseline | CRT | P | |
| Mean strain peaks (%) | −11.3 ± 2.5 | −12.2 ± 2.8 † | .008 | −11.2 ± 2.2 | −10.4 ± 1.6 | .03 |
| SD t,peak (msec) | 115 ± 49 ∗ | 72 ± 35 † | <.0001 | 93 ± 49 | 93 ± 51 | .98 |
| Mean I L,avc (% · sec −1 ) | 1.10 ± 0.66 | 1.38 ± 0.75 † | .001 | 1.08 ± 0.58 | 0.96 ± 0.57 | .22 |
| Mean I L,peak (% · sec −1 ) | 1.75 ± 0.74 | 1.90 ± 0.75 † | .06 | 1.67 ± 0.66 | 1.55 ± 0.54 | .34 |
| SD of I L,peak (% · sec −1 ) | 1.15 ± 0.57 ∗ | 0.99 ± 0.48 | .02 | 0.92 ± 0.52 | 0.92 ± 0.49 | .97 |
| SD of I L,avc (% · sec −1 ) | 1.09 ± 0.51 | 1.01 ± 0.50 | .28 | 1.02 ± 0.39 | 0.98 ± 0.46 | .50 |
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