Role of Left Ventricular Strain Imaging in Patients Undergoing Cardiac Resynchronization Therapy

Manish Bansal

doi:10.4103/jiae.jiae_50_23

REVIEW ARTICLE

Year : 2023 | Volume : 7 | Issue : 2 | Page : 154-160

Role of Left Ventricular Strain Imaging in Patients Undergoing Cardiac Resynchronization Therapy

Manish Bansal
Department of Cardiology, Medanta Heart Institute, Medanta - The Medicity, Gurugram, Haryana, India

Date of Submission	18-Aug-2023
Date of Acceptance	23-Aug-2023
Date of Web Publication	30-Aug-2023

Correspondence Address:
Manish Bansal
Department of Cardiology, Medanta Heart Institute, Medanta - The Medicity, Sector 38, Gurugram - 122 001, Haryana
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiae.jiae_50_23

Abstract

Lack of therapeutic response in nearly 30% of patients undergoing cardiac resynchronization therapy (CRT) remains a major therapeutic challenge. Given the role of echocardiography in detecting mechanical dyssynchrony, extensive research has been undertaken to identify the echocardiographic predictors of CRT response. After the initial setback, the interest in this field has renewed with the introduction of speckle-tracking echocardiography (STE) for quantifying myocardial deformation. Several newer and potentially useful indices of mechanical dyssynchrony have been developed. In addition, the non-invasive assessment of myocardial work has also become feasible and many of the myocardial work indices have shown considerable promise in the initial studies. The strain imaging may also help in identifying the optimum site for left ventricular lead placement. This review summarizes the current understanding regarding the role of left ventricular strain imaging in patients undergoing CRT.

Keywords: Apical rocking, mechanical dyssynchrony, septal flash, systolic stretch index, wasted work

How to cite this article:
Bansal M. Role of Left Ventricular Strain Imaging in Patients Undergoing Cardiac Resynchronization Therapy. J Indian Acad Echocardiogr Cardiovasc Imaging 2023;7:154-60

How to cite this URL:
Bansal M. Role of Left Ventricular Strain Imaging in Patients Undergoing Cardiac Resynchronization Therapy. J Indian Acad Echocardiogr Cardiovasc Imaging [serial online] 2023 [cited 2023 Sep 27];7:154-60. Available from: https://jiaecho.org/text.asp?2023/7/2/154/384778

Introduction

In patients with symptomatic heart failure (HF) due to left ventricular (LV) systolic dysfunction associated with wide QRS on electrocardiogram [predominantly left bundle branch block (LBBB)], cardiac resynchronization therapy (CRT)improves LV systolic function and significantly reduces morbidity and mortality.^[1] For this reason, in appropriately selected patients, all the major clinical practice guidelines assign class I or at least class IIa recommendation to CRT.^[2],[3],[4] However, despite selecting the patients according to the defined criteria, approximately 30% of patients fail to benefit from the therapy.^[5] Prediction of this lack of response to CRT has been a subject of intensive research over the past more than two decades.

The initial recognition that electrical dyssynchrony did not necessarily mean mechanical dyssynchrony led to a lot of interest in using echocardiography for detecting mechanical dyssynchrony as a predictor of response to CRT. Several different echocardiographic indices were developed which were tested mostly in single-center studies and were shown to be of benefit. However, subsequently a large, prospective, multicentric study-the Predictors of Response to CRT (PROSPECT) trial– revealed that none of the echocardiographic parameters was sufficiently robust for routine clinical application.^[6] As a result, the interest in echocardiography for patient selection for CRT gradually waned.

During the last two decades, strain imaging has emerged as a useful modality for objective assessment of myocardial contractile function. Although Doppler-based strain was developed first, speckle tracking echocardiography (STE) is the technique used currently for this purpose. STE is a grayscale-based technique that can quantify myocardial deformation using the conventional two-or three-dimensional grayscale echocardiography images. A comprehensive, multi-dimensional analysis of the myocardial deformation can easily be performed.

The advent of strain imaging has reignited interest in evaluating the utility of echocardiography for optimizing patient selection for CRT. In addition, strain imaging can also help in predicting overall clinical outcomes and guiding LV lead placement. This review summarizes the current understanding in this field. Although strain imaging can also be used for quantifying right ventricular and left atrial deformation, this review focuses primarily on the role of LV strain imaging in patients undergoing CRT.

Prediction of Response to Cardiac Resynchronization Therapy

Global longitudinal strain as a predictor of outcomes

The likelihood of a favorable response to CRT decreases as the left ventricle becomes progressively dilated and dysfunctional. Since a very low LV global longitudinal strain (GLS) indicates a markedly dysfunctional left ventricle, it also predicts a higher likelihood of non-response to CRT and worse clinical outcomes.

Cimino et al. studied 24 consecutive patients undergoing CRT. It was found that all the echocardiographic features indicating advanced LV remodeling (higher LV volumes, lower LV ejection fraction [LVEF], and lower GLS) were associated with a lack of response to CRT. In contrast, none of the markers of mechanical dyssynchrony predicted CRT response.^[7] In another study, the baseline GLS with a cut-off value of -12% was found to be the strongest predictor of CRT super-responders.^[8] Recently, a meta-analysis was performed which included 12 studies with 1004 patients. The baseline GLS values were significantly associated with the response to CRT.^[9]

In addition to predicting response to CRT, GLS is also an excellent predictor of clinical outcomes. In a study of 205 patients undergoing CRT, a GLS value less negative than-9% was associated with a higher incidence of both the primary (a combination of death, circulatory support, or transplant) and secondary (HF hospitalization or death) endpoints. The reduced global circumferential strain (GCS, less negative than-9%) also showed similar associations.^[10] A large study which included 829 patients undergoing CRT also showed that baseline GLS was associated with the incidence of primary endpoint (a combination of all-cause mortality, heart transplantation, and LV assist device implantation). The patients in the worst GLS quartile had two times higher risk of reaching the primary endpoint compared with those in the best GLS quartile.^[11] Park et al. combined GLS with other relevant echocardiographic parameters to develop a multiparametric score which was helpful not only in predicting reverse remodeling after CRT but also in predicting the clinical outcomes.^[12] Interestingly, a low GLS also predicts clinical outcomes in patients with narrow QRS (<130 ms) and may even predict harm with CRT in these patients. In one such study, the patients in the lowest GLS quartile had a higher incidence of the combined primary endpoint of all-cause mortality and HF hospitalization when CRT was turned on.^[13]

Strain dispersion

The initial approaches to echocardiographic assessment of mechanical dyssynchrony relied on analyzing the dispersion in the time to peak segmental velocity. A delay of >60-65 ms in the time to peak systolic velocity of the opposing wall segments could predict CRT response.^[14],[15] Similarly, the standard deviation of the time to peak velocity of all the LV segments, known as the Yu index, was also found to be a good predictor of response to CRT.^[16],[17] A similar approach has been applied to strain imaging also to assess mechanical dyssynchrony and to predict the response to CRT.

Numerous studies performed over the years have shown that dispersion in the peak segmental longitudinal, radial, or circumferential strain is associated with a higher likelihood of response to CRT.^{[18],[19],[20],[21],[22],[23],[24],[25]} Furthermore, strain dyssynchrony seems to have a better performance than the dyssynchrony assessed using tissue velocity imaging.^[20],[21] Radial dyssynchrony appears to be the most robust [Figure 1].^{[18],[19],[22]} A cut-off value of >130 ms delay in the time to peak segmental radial strain (analyzed in the midventricular short-axis view) has been shown to have 83% sensitivity and 80% specificity for predicting CRT response.^[18],[22]

Figure 1: Strain dispersion assessed using radial strain in the mid short-axis view of the left ventricle (LV). (a) A synchronously contracting LV with all the myocardial segments peaking almost at the same time. (b) A markedly dyssynchronous LV with a delay of 130 ms in the peak radial strain of the mid anterior septum (yellow curve) and the posterior wall (magenta curve). AVC: Aortic valve closure

Click here to view

Lim et al. used a different approach to quantify strain dyssynchrony. In a study of 235 patients undergoing CRT, they calculated strain-delay index as the sum of the difference between the end-systolic and the peak longitudinal strain across the 16 segments. The time to peak segmental longitudinal strain was also calculated. The strain delay index was found to be the strongest predictor of response to CRT.^[26] In another study, a similar approach was applied to radial strain assessed in the midventricular short-axis view. Both the baseline radial strain dyssynchrony and its acute reduction with CRT were associated with a good response to CRT in the long term.^[27] Inden et al. developed a new index (i-index) which combined segmental dyssynchrony with contractility. It was calculated as the product of the standard deviation of the time to peak systolic radial strain of the six mid-LV segments and the mean radial strain of the same segments. It was found that a cutoff value of i-Index >2000 predicted responders with 94% sensitivity and 80% specificity and was superior to radial dyssynchrony alone.^[28]

Abnormal contraction patterns

A typical LBBB is associated with a characteristic contraction pattern of the left ventricle. The septum exhibits a brief shortening during the pre-ejection phase followed by stretching. In contrast, the LV lateral wall initially undergoes a brief stretching followed by late systolic shortening. This abnormal contraction pattern results in several echocardiographic findings that can help in predicting the response to CRT.

Septal flash (SF) is the brief pre-systolic or early systolic contraction of the septum, which can be visually recognized in the apical four-chamber view or by using M-mode in the parasternal long-axis view. Apical rocking is the rocking motion of the LV apex visualized in the apical four-chamber view. It results from the sequential, instead of simultaneous, contraction of the septum and the lateral wall [Video 1]. PREDICT-CRT was a large multicentric study that retrospectively analyzed data from 1060 patients undergoing CRT. Apical rocking and SF were visually assessed before device implantation and at 12 ± 6 months post-implantation. Apical rocking was observed in 64% of patients and SF in 63%. The absence of apical rocking and SF as well as their persistence after device implantation were both associated with a high risk for non-response to CRT and an unfavorable long-term survival.^[29] There are other studies also that have demonstrated the prognostic utility of these findings.^[30],[31]

Video 1: The apical four-chamber view showing the classical apical rocking in a patient with left bundle branch block.

With the availability of STE, it is now feasible to characterize the LBBB-related abnormal septal contraction pattern more objectively. Based on the longitudinal strain curves of the basal/mid septum, 3 different patterns can be recognized [Figure 2]: pattern 1- double-peaked systolic shortening; pattern 2- early pre-ejection shortening peak followed by prominent systolic stretch, and pattern 3- pseudonormal shortening with a late systolic shortening peak. The first two patterns are highly predictive of CRT response.^[31],[32] These patterns are also associated with a significantly lower risk of all-cause and cardiac mortality and HF hospitalization after CRT.^[33]

Figure 2: Different septal strain patterns seen in the presence of left bundle branch block. (a) Double-peaked systolic shortening (light blue curve); (b) Early pre-ejection shortening peak followed by prominent systolic stretch (light blue curve), and (c) pseudonormal shortening with a late systolic shortening peak (yellow curve). The contraction pattern shown in (b) is also considered the classical left bundle branch block pattern characterized by early septal shortening with early stretching and late shortening of the lateral wall (dark blue curve). AVC: Aortic valve closure

Click here to view

Combining LV lateral wall longitudinal strain curves with the septal strain curves can help further refine the contraction pattern associated with LBBB. A classical LBBB contraction pattern is one in which the septal peak shortening occurs within the initial 70% of the ejection phase, whereas the lateral wall is initially stretched followed by shortening that peaks after the aortic valve closure [Figure 2]b. The presence of such a contraction pattern is highly predictive of response to CRT and is superior to time-to-peak methods.^[34],[35] However, it may suffer from suboptimal inter-reader agreement.^[35]

More recently, different approaches have been developed to quantify the stretching of the septum and the lateral wall. In a study of 442 patients undergoing CRT, Gorcsan III et al. developed a novel computer program to semiautomatically calculate systolic-stretch index (SSI) [Figure 3]. SSI was calculated as the sum of the posterolateral wall stretch during the pre-ejection period and the septal rebound stretch during the ejection phase. A high SSI derived from the longitudinal strain curves was associated with a significantly lower risk for HF hospitalization or death. This prognostic utility was also seen in patients with QRS 120 to 149 ms or non-LBBB pattern on electrocardiogram.^[36] In other studies, only the septal systolic stretch was quantified and was found to be an independent predictor of CRT response.^[37],[38]

Figure 3: Estimation of septal stretch and systolic stretch index from the longitudinal strain curves in the apical four-chamber view. The yellow lines indicate the extent of systolic septal stretch whereas the red line indicates the presystolic lateral wall stretch. Please see the text for more details. AVC: Aortic valve closure

Click here to view

Myocardial work assessment

One of the major limitations of strain imaging is that much like tissue velocity, strain is also load dependent. The recently developed technique of myocardial work (MW) assessment using STE overcomes this limitation by integrating LV longitudinal strain (a surrogate for LV preload) and systolic blood pressure (a surrogate for LV afterload). From the pressure-strain loops thus created, several indices of segmental and global MW can be derived including total work, wasted work, constructive work, work efficiency, and segmental work asymmetry [Figure 4]. The initial experience with this technique has shown that MW can help predict the response to CRT.

Figure 4: Myocardial work estimation using speckle-tracking echocardiography in a patient with left bundle branch block. (a) Red curve depicts the global pressure-strain loop, whereas the green curve depicts the markedly abnormal basal septal pressure-strain loop. (b) The red curve is same as above, but the green curve here depicts the pressure-strain loop from the basal lateral wall. A marked difference between the contraction patterns of the septal and lateral wall can be noted. The global wasted work is increased (333 mmHg%). BP: Blood pressure, GCW: Global constructive work, GLS: Global longitudinal strain, GWE: Global work efficiency, GWI: Global work index, GWW: Global wasted work

Click here to view

In an early study of 21 patients, it was observed that the septal wasted work and the wall motion score index were the only significant predictors of response to CRT, with a combination of the two yielding an area under the curve of 0.86.^[39] A recent, much larger study of 248 patients demonstrated the predictive value of global wasted work (GWW) for this purpose. A cut-off value of GWW >200 mmHg% independently predicted CRT response with 85% specificity and 50% sensitivity. Furthermore, a GWW <200 mmHg% was also associated with an increased risk for all-cause mortality during the follow-up.^[40] In another study, global constructive work was found to be a predictor of CRT response. Global constructive work <1057 mmHg% identified 85% of non-responders with a positive predictive value of 88%.^[41] In another study from the same group, a combination of the constructive work >1057 mmHg% and the wasted work >384 mmHg% provided 100% specificity and positive predictive value for predicting CRT response, but the sensitivity was low (22%).^[42]

MW seems to be useful even in patients with QRS morphologies not ideal for CRT. A very recent study included 121 such patients of whom 68 (56%) showed improvement with CRT. The GWW ≥200 mmHg% and certain specific longitudinal strain septal contraction patterns were predictive of CRT response. The same parameters also predicted survival free from death or HF hospitalization over a follow-up period of 46 months.^[31]

In another study, the investigators combined MW assessment with cardiac magnetic resonance (CMR)-based assessment of septal viability. The presence of work difference between the septum and LV lateral wall combined with the septal viability was significantly associated with CRT response.^[43] It also predicted long-term survival without heart transplantation.

Many other studies have shown that global LV MW indices such as low constructive work, low MW efficiency, and low wasted work are associated with a high risk for cardiac and all-cause mortality in patients undergoing CRT.^{[31],[40],[44],[45]}

Guiding Left Ventricular Lead Placement

Incorrect LV lead placement is one of the reasons underlying the failure to respond to CRT. To derive the maximum benefit from CRT, it is imperative to pace the segments which are not scarred and have the most delayed electrical activation. Radial strain imaging can help in identifying the optimum site for LV lead placement because it can assess both the extent of scarring and the timing of contraction. The information obtained from the strain imaging can be overlayed onto the fluoroscopic images to select the most appropriate vein for LV lead placement. Although it may not always be possible to position the LV lead exactly at the desired site, closer the placement, better the outcome.

The Speckle Tracking Assisted Resynchronization Therapy for Electrode Region (STARTER) was a prospective, randomized controlled trial which included 187 patients undergoing CRT. Time to peak radial strain was used to identify the site of the latest mechanical activation. Of the 187 patients, 110 were randomized to echocardiography-guided LV lead placement in whom an attempt was made to position the lead as close to the latest activated segment as possible. In the remaining 77 patients, the LV lead was positioned in the usual manner. It was found that the echocardiography-guided LV lead placement resulted in a significantly lower incidence of first HF hospitalization or death. The LV lead could be placed exactly concordant or adjacent to the latest activated segment in 85% of patients in the echocardiography-guided group whereas it occurred fortuitously in 66% of the controls. Compared with the remote placement, concordant or adjacent LV lead placement was associated with significantly better clinical outcomes.^[46] A subsequent analysis of the same study showed that the peak segmental radial strain >10% (indicating the absence of scarring) at the site of LV lead was also independently associated with a favorable outcome.^[47]

Similar findings were observed in the Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy (TARGET) study which randomized 220 patients to echocardiography-guided versus conventional LV lead placement. In this study, both the timing and the magnitude of radial strain were considered to select the optimum site for LV lead placement. The patients in the TARGET group had a greater reduction in LV end-systolic volume and a lower incidence of the combined endpoint of HF hospitalization and death. In addition, the placement of LV lead away from the optimum site or within a scarred segment was associated with higher all-cause mortality.^[48] The survival benefit with optimum LV lead placement persisted even after a median follow-up of 39 months.^[49] There are other studies also which have shown the benefits of LV lead guidance using strain imaging.^{[50],[51],[52]} Some of these studies used nuclear imaging or CMR instead of the peak amplitude of radial strain to assess the segmental viability.^[51],[52] In contrast, there are other studies that did not find any benefit with radial strain-guided LV lead placement, with or without multimodality imaging.^[53],[54]

Limitations and the Way Forward

The PROSPECT study had shown that all the echocardiographic variables of mechanical dyssynchrony available at that time had high degree of observer variability and sub-optimal predictive accuracy.^[6] STE-based strain imaging has been used as a means to overcome this limitation. However, dyssynchrony assessment requires segmental strain analysis and the segmental strain unfortunately has high measurement variability at present. Therefore, even though many studies have shown the potential utility of strain imaging in predicting CRT response, large prospective studies are needed to accurately define the reliability and robustness of these parameters. The role of multimodality imaging also needs to be defined better. In this regard, a large European multicenter prospective observational study is currently underway to evaluate the prognostic value of STE-based dyssynchrony and MW assessment combined with CMR-based scar assessment in patients undergoing CRT.^[55]

Segmental strain analysis is time-consuming and the measurement of many of the dyssynchrony indices is technically quite challenging as well. The use of automated methods for image analysis and interpretation can help in this.^[24],[36] The application of machine learning can further help by allowing the incorporation of a wide range of clinical and echocardiographic parameters to improve the identification of CRT responders.^[56],[57]

In addition to the LV size, systolic function, and contractile pattern, the status of the left atrium and right ventricle also influences the response to CRT. The role of left atrial size, left atrial strain and right ventricular strain was outside the scope of this review, but there are studies exploring the role of these parameters also.^{[12],[58],[59]}

Conclusions

In patients with symptomatic HF with reduced LVEF, the indication for CRT is currently based only on QRS morphology and duration. However, nearly one-third of the patients undergoing CRT as per the current indications fail to benefit from the therapy. Several studies have shown that echocardiography can help in this setting by optimizing the patient selection for CRT. However, the significant measurement variability of the echocardiographic parameters used for the assessment of mechanical dyssynchrony has been a major limitation. With the advent of STE, many newer indices have been developed which may be more accurate for predicting CRT response. MW assessment is also feasible with STE and has shown promise. In addition, STE may also help in guiding LV lead placement. The incorporation of these newer echocardiographic parameters along with the use of automated image analysis tools, incorporation of multimodality imaging, and the application of machine learning approaches for easy integration of multidimensional data should eventually help develop a robust methodology for optimum selection of the patients for CRT.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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