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Circulation: Cardiovascular Imaging. 2008;1:79-85
doi: 10.1161/CIRCIMAGING.108.792804
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Controversies in Imaging

Is echocardiographic assessment of dyssynchrony useful to select candidates for cardiac resynchronization therapy?

Echocardiography Is Useful Before Cardiac Resynchronization Therapy if QRS Duration Is Available

Jacob Abraham, MD and Theodore P. Abraham, MD

From the Translational Cardiovascular Ultrasound Laboratory, Division of Cardiology, Johns Hopkins University, Baltimore, Md.

Correspondence to Theodore P. Abraham, MD, Johns Hopkins University, 600 N Wolfe St, Carnegie 568, Baltimore, MD 21287. E-mail tabraha3{at}jhmi.edu


   Introduction
TOP
 Introduction
Rationale for Evaluating...
 Limitations and Challenges of...
 Moving Forward After PROSPECT...
 References
 References 
 
Cardiac resynchronization therapy (CRT) has emerged as one of the few therapies available for patients with advanced heart failure (HF) that favorably affects symptoms, functional status, hospitalization rates, and mortality rate.1,2 It is thought that CRT achieves these benefits by coordinating contraction between ventricular segments that at baseline are dyssynchronous.3 Synchronized electrical excitation of the ventricles leads to near-simultaneous mechanical activation of the normal and delayed segments, resulting in greater stroke volume and reduction of mitral regurgitation with improved neurohormonal profile and reversal of adverse ventricular remodeling. The early large-scale clinical trials that established these benefits of CRT were limited to patients with prolonged QRS duration, a simple and convenient marker of delayed electrical activation. On the basis of these data, current guidelines recommend CRT for patients with ejection fraction <35%, moderate to severe symptoms (New York Heart Association class III to IV), and QRS >120 ms.

Response by Prinzen and Auricchio p 84

A consistent finding from all trials of CRT, however, is a lack of clinical or echocardiographic benefit in approximately one third of patients ("nonresponders").4 Unlike pharmacological therapy, CRT is complex, invasive, and costly; therefore, improved identification of patients likely to benefit is a clinical imperative. One factor among many underlying this high rate of nonresponse is that QRS duration is an imperfect surrogate for the disorder actually targeted by CRT: mechanical dyssynchrony. Mechanical dyssynchrony may involve delay in mechanical activation of the left ventricle (LV) relative to the right ventricle (RV) (interventricular dyssynchrony) or of one LV region relative to another (intraventricular dyssynchrony).

Several lines of evidence suggest that QRS duration may not always be concordant with mechanical dyssynchrony. Leclercq et al5 used an experimental model of tachypacing-induced HF with left bundle-branch block to demonstrate improvement in invasive indices of ventricular contractility after CRT with no change in electrical dyssynchrony. These findings suggest a disconnect between electrical and mechanical activity. Furthermore, small studies using tissue Doppler imaging (TDI)–based evaluation of mechanical activity demonstrate a low concordance between QRS duration and mechanical dyssynchrony. Up to 30% of HF patients with normal QRS duration may have significant mechanical dyssynchrony; conversely, 20% to 30% of HF patients with wide QRS duration may not have mechanical dyssynchrony.6 Taken together, these lines of evidence suggest that QRS duration is not closely related to mechanical dyssynchrony, and therefore it is not surprising that baseline QRS duration is not the best predictor of response to CRT.

Several reports have examined the significance of demonstrating mechanical dyssynchrony and its possible use in predicting response to CRT. Almost all of these studies used TDI-based criteria to evaluate dyssynchrony and have generated a number of potential dyssynchrony indices. In general, these indices demonstrate either a time delay in mechanical activation between segments of the LV (septal to lateral wall delay in time to peak systolic tissue velocity) or substantial dispersion of mechanical activation (standard deviation of time to peak systolic tissue velocity).7,8 Because of space constraints, we will not delve into details of individual parameters or cover the technical details of the manner in which individual measurements are performed. These topics have been well described in other recent reviews and the original articles.9–11

A number of small, mostly single-center studies have suggested that a septal to lateral or opposing segment delay of 65 ms predicts response to CRT. Similarly, a standard deviation of time to peak tissue velocity >32 ms appears to predict response. Response in most studies was defined by clinical improvement and/or presence of reverse remodeling as demonstrated by echocardiography. In these small, nonrandomized, nonblinded, and retrospective studies, the reported cutoff values appear to be superior to QRS duration and several other conventional echocardiographic parameters in predicting response to CRT. These findings suggest that echo-derived parameters may be an efficient method of selecting patients for CRT. More recently, however, 2 recent large, multicenter, prospective studies—Predictors of Response to CRT (PROSPECT) and Resynchronization Therapy in Narrow QRS Study (ReThinQ) used echocardiographic criteria to select patients for CRT and found no correlation between echo-based indices of mechanical dyssynchrony and CRT benefit, raising questions about the need for echocardiography in selecting patients for CRT.

In this perspective, we present arguments for the continued use of techniques to demonstrate mechanical dyssynchrony before referring patients to CRT. At the outset, we emphasize that in the absence of rigorous, adequately powered, controlled studies using echo-based dyssynchrony to randomize patients to CRT versus no CRT, patients fulfilling the original clinical criteria for CRT should not be refused CRT. Even so, clinicians applying these clinical criteria should be prepared for 3 of 10 patients to show no response to CRT.

We will address the controversy by discussing 3 issues: (1) the rationale for evaluating mechanical dyssynchrony in HF, (2) the limitations and challenges of dyssynchrony analysis by echo, and (3) moving forward after PROSPECT and ReThinQ?


   Rationale for Evaluating Mechanical Dyssynchrony in HF
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 Introduction
 Rationale for Evaluating...
Limitations and Challenges of...
 Moving Forward After PROSPECT...
 References
 References 
 
As mentioned earlier, QRS duration correlates only weakly with mechanical dyssynchrony. The duration of the QRS complex on the surface ECG reflects the duration of total ventricular (RV and LV) electrical activation. On the one hand, rapid RV depolarization can offset delays in LV activation, resulting in normal QRS width. In addition, distal conduction disease may not manifest on the surface ECG. In both situations, significant mechanical dyssynchrony could be present despite a normal QRS. On the other hand, widening of the QRS complex might be a reflection of diffuse conduction disturbance or primarily RV delay with little LV mechanical dyssynchrony. Using TDI to measure temporal delay between septal and lateral wall peak systolic velocity, Bleeker et al6 found that 70% of patients with QRS duration >150 ms had severe mechanical dyssynchrony compared with 27% of patients with a normal QRS width. When QRS duration was analyzed as a continuous variable in this study, however, there was no relationship between QRS duration and extent of LV dyssynchrony. Yu et al12 confirmed a similar rate of mechanical dyssynchrony in a group of patients with HF and wide QRS yet found a 51% prevalence of mechanical dyssynchrony in a narrow-QRS patient cohort. These observations suggest that although a particularly wide QRS complex (>150 ms) confers a greater likelihood of CRT response, patient selection based solely on QRS duration could result in significant overtreatment of one group of patients (QRS >120 ms) with simultaneous undertreatment of another group (QRS ≤120 ms).

Does the presence of mechanical dyssynchrony predict response to CRT better than baseline QRS duration? Nelson et al13 studied the acute response to multisite pacing using invasive pressure measurements in 22 patients with dilated cardiomyopathy and QRS >140 ms. The extent of mechanical dyssynchrony, indexed by circumferential strain derived from tagged MRI, was a stronger predictor of systolic augmentation than basal QRS width (r=0.88 versus r=0.55). The chronic response to CRT was compared in a nonrandomized trial between comparable groups of patients with dilated cardiomyopathy and either wide (>120 ms) or narrow QRS (≤120 ms). Despite this difference in QRS duration, both groups had similar degrees of interventricular and intraventricular dyssynchrony by Doppler/M-mode echocardiography, and at 6 months they achieved similar clinical and echocardiographic improvements.14 Similarly, data from a multitude of TDI-based studies support the general concept.7,11,15,16 Among the numerous indices of mechanical dyssynchrony that have been proposed, the criteria commonly used are septal to lateral wall delay >65 ms and standard deviation of time to peak systolic velocity of 12 segments >33 ms. The relative value of TDI versus strain/strain rate in predicting response to resynchronization has not been fully resolved. Although these studies are limited by small numbers of patients, they provide convincing evidence supporting the hypothesis that mechanical dyssynchrony predicts response to CRT.

Moreover, analysis of myocardial mechanics after CRT suggests that the primary mechanism of improved LV performance is mechanical synchrony. Takemoto et al17 showed that improvements in LV function in patients with HF and narrow QRS duration were related to reduced dyssynchrony rather than improved regional function. We have recently corroborated these data in an animal model of tachypacing-induced HF with a wide QRS duration, demonstrating improved LV performance coincident with improvements in mechanical dyssynchrony by echocardiography despite negligible if any change in regional contractility.18,19 Thus, the available data appear to strongly support a cause-and-effect relationship between mechanical dyssynchrony and CRT. Restoration of mechanical synchrony is associated closely with improvement in LV function. Therefore, the presence of mechanical dyssynchrony is necessary for patients to derive the best results from CRT. Limited studies suggest that CRT may be detrimental in the absence of dyssynchrony, and therefore it may not be prudent to treat all patients on the basis of QRS width. In a small, retrospective study, patients without dyssynchrony subjected to CRT had more adverse events than did those with dyssynchrony.15


   Limitations and Challenges of Dyssynchrony Analysis by Echo
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 Introduction
 Rationale for Evaluating...
 Limitations and Challenges of...
Moving Forward After PROSPECT...
 References
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In view of ReThinQ and PROSPECT, we are faced with a paradox. On one hand, substantial and convincing data indicate that TDI-derived dyssynchrony indices predict response to CRT. On the other hand, the only randomized and blinded studies suggest otherwise. Mechanical dyssynchrony is a necessary substrate for CRT.11 However, there are several reasons that the proposed criteria for diagnosing mechanical dyssynchrony may not be valid. Most relate to a number of technical and interpretative challenges routinely encountered in dyssynchrony analysis. These difficulties have been detailed elsewhere previously.9 With either tissue velocity or strain, there is considerable sensitivity of the signal amplitude and phase (timing) to the position of the sample region. Small changes in position often result in significant changes in peak velocity, number of peaks, signal fidelity, and timing of the peak. Similarly, tissue Doppler velocities and strain demonstrate dependence on the angle of insonation when full-sector images are used. Tissue velocity tracings often yield multiple systolic peaks within a single cardiac cycle (Figure, A and B). Determining which of these peaks is physiological versus noise is challenging and requires that the operator integrate information from deformation/velocity/strain/strain rate curves. In some difficult cases, it may not be possible to adjudicate the "physiological" peak. There is a general lack of consensus within the field about how best to resolve this problem. Additionally, TDI tracings may lack a distinct peak (domed peak), making it difficult to measure timing accurately (Figure, C). As a consequence, considerable intraobserver and interobserver variability exists, even within the context of clinical trials by experienced echocardiographers. Differences and the relative incremental value of tissue velocity versus strain rate or strain have not been thoroughly and rigorously examined.


Figure 1792804
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  		Figure. A, Tissue velocity tracings from a normal subject show near-simultaneous mechanical activation of the septum (yellow) and lateral wall (green). Vertical dashed lines indicate aortic valve opening (AVO) and aortic valve closure (AVC). B, Example of multiple systolic peaks in the lateral wall (white arrows) compared with the single midsystolic septal peak (yellow arrow). Depending on which peak is picked, the time delay will be normal or dyssynchronous. C, Example of a "domed" peak (white arrow). Again, it is challenging to adjudicate the true peak, and this can cause substantial variability in timing measurement.

 
In addition to all of these challenges, it is our opinion that due diligence has not been performed on certain conceptual issues. We have resorted to using tissue velocity for dyssynchrony analysis without first establishing whether tissue velocity is indeed the best metric for mechanical activity. After all, tissue velocity merely tracks motion, whereas the heart does not just move—it deforms. Strain rate and strain track deformation and have been shown to be superior to TDI in evaluating regional mechanics.20–22 Strain by magnetic resonance has been used as the primary measure of dyssynchrony in experimental models.23 A recent article suggests that strain-derived dyssynchrony indices may be superior to TDI indices.24

These questions include how to assess regional mechanics before and after CRT, and how best to adjudicate multiple systolic peaks. We cannot condemn TDI if we cannot implement it appropriately, yet we cannot implement TDI appropriately without a better understanding of its application in HF.


   Moving Forward After PROSPECT and ReThinQ
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 Introduction
 Rationale for Evaluating...
 Limitations and Challenges of...
 Moving Forward After PROSPECT...
References
 References 
 
The ReThinQ study enrolled 172 patients who had a standard indication for an implantable cardioverter-defibrillator and randomly assigned them to CRT or no CRT for 6 months. The primary end point was the proportion of patients with an increase in peak oxygen consumption of ≥1.0 mL/kg body wt per minute during cardiopulmonary exercise testing at 6 months. Both groups did not differ significantly in the proportion of patients with the primary end point (46% and 41%, respectively).25 The peak oxygen consumption increased in a subset of patients with QRS duration ≥120 ms (P=0.02) but was unchanged in the group with QRS duration <120 ms (P=0.45). The authors concluded that patients with HF and narrow QRS intervals may not benefit from CRT.

The PROSPECT trial was a much larger study that enrolled 498 patients with standard CRT indications from 53 centers in Europe, Hong Kong, and the United States.26 Twelve echocardiographic parameters of dyssynchrony, based on both conventional echocardiography and TDI-based methods, were evaluated. The end points were an improved clinical composite score and ≥15% reduction in LV end-systolic volume at 6 months. Clinical composite score was improved in 69% of 426 patients, whereas LV end-systolic volume decreased ≥15% in 56% of 286 patients with paired data. The sensitivity ranged from 6% to 74% and specificity from 35% to 91% to predict clinical composite score. The sensitivity ranged from 9% to 77% and specificity from 31% to 93% for prediction of a ≥15% decrease in LV end-systolic volume. There was wide variability in the performance characteristics of each dyssynchrony parameter.

Superficially, there are 2 potential conclusions from these data: (1) CRT is not an effective therapy in patients with narrow QRS duration–related HF, and (2) echocardiographic measures of dyssynchrony are not efficient predictors of CRT response. However, given all we have presented in the preceding paragraphs, we submit that either of these conclusions would be imprecise. Indeed, for those of us who have practiced and endured the art of TDI and strain imaging for some time, these results are not at all surprising. We have already presented our views on the myriad challenges with TDI or strain imaging. However, it would be inaccurate to conclude that TDI- and strain-derived dyssynchrony analysis is not feasible in clinical practice. Instead, we believe that echocardiographic evaluation of dyssynchrony and, more precisely, its application to dyssynchrony analysis are not mature at present. Indeed, it would be shortsighted and unwise to abandon assessment of mechanical dyssynchrony. As stated before, dyssynchrony appears to be a necessary substrate for CRT with quantifiable resynchronization associated with improvements in LV function.

So how do we proceed at this time? Many basic questions need to be addressed with the use of more robust techniques, including strain analysis, before additional clinical trials are begun. These include the assessment of changes in regional mechanics before and after CRT and how to best adjudicate multiple systolic peaks. We cannot condemn the technique if we cannot implement it appropriately, and we cannot implement it appropriately if we do not understand the fundamental mechanics in HF using these techniques and their evolution with CRT. Ongoing and extensive experience with these techniques will enable a wider audience to develop expertise in these novel methods. Technological advances leading to less operator-dependent analysis of regional mechanics will substantially improve the reproducibility and clinical application of TDI and strain.

Finally, it is overly simplistic to assume that a single echocardiographic parameter will best predict response to CRT. The patient substrate in CRT is complex, and multiple factors influence the final response to CRT. All of these factors must be considered to decide the best course of action for a particular patient. Some of these factors include the following: (1) etiology of HF; (2) location of LV lead; (3) presence of scar and myocardial viability; and (4) timing and method of pacemaker optimization. Ischemic etiology, anterior locations of the LV lead, presence of scar in the implant area, and suboptimal pacemaker settings have all been associated with a poor response to CRT.27–30 There is also an effort to evaluate for presence of myocardial viability before CRT.31

We foresee that a multifactor dyssynchrony score will likely emerge as the best predictor of response to CRT. This score will incorporate clinical factors, QRS duration, and multiple imaging parameters. Imaging parameters may not be restricted to intraventricular dyssynchrony alone and may include flow Doppler and TDI measurements of interventricular dyssynchrony. Such an approach will likely reveal that the presence of myocardial dyssynchrony is a heavily weighted component in this score and a required substrate. Post-CRT optimization may emerge as another important factor because it is not reasonable to draw conclusions on response to CRT without assessing whether the electrical therapy is being applied appropriately.

In conclusion, CRT is an important therapeutic advance in the treatment of patients with HF. As with all therapies, particularly invasive and expensive ones, accurate patient selection leads to maximal clinical benefits, optimal risk/benefit profile, and a cost-effective implementation of the technology. Ample data suggest that mechanical dyssynchrony is likely a critical substrate for CRT efficacy. An accurate, reliable, and routinely feasible assessment of mechanical dyssynchrony is needed to bridge the gap between theory and practice. Technological and methodological issues currently limit the of dyssynchrony analysis routine use of dyssynchrony analysis. However, advances in engineering, analysis software, and our understanding of regional myocardial deformation should take dyssynchrony assessment beyond the surface ECG. In the meantime, judicious and thoughtful use of dyssynchrony analysis is warranted.


   Acknowledgments
 
We thank Veronica L. Dimaano, MD, and Aurelio C. Pinheiro, MD, PhD, for their assistance with this manuscript.

Sources of Funding

This work was supported in part by grants from the National Institutes of Health (AG22554 and HL076513).

Disclosures

None.


   References
TOP
 Introduction
 Rationale for Evaluating...
 Limitations and Challenges of...
 Moving Forward After PROSPECT...
 References
References 
 

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  6. Bleeker GB, Schalij MJ, Molhoek SG, Verwey HF, Holman ER, Boersma E, Steendijk P, Van Der Wall EE, Bax JJ. Relationship between QRS duration and left ventricular dyssynchrony in patients with end-stage heart failure. J Cardiovasc Electrophysiol. 2004; 15: 544–549.[Medline]
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  8. Yu CM, Fung JW, Zhang Q, Chan CK, Chan YS, Lin H, Kum LC, Kong SL, Zhang Y, Sanderson JE. 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.[Abstract/Free Full Text]
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  11. Bax JJ, Abraham T, Barold SS, Breithardt OA, Fung JW, Garrigue S, Gorcsan Jr, Hayes DL, Kass DA, Knuuti J, Leclercq C, Linde C, Mark DB, Monaghan MJ, Nihoyannopoulos P, Schalij MJ, Stellbrink C, Yu CM. Cardiac resynchronization therapy, part 1: issues before device implantation. J Am Coll Cardiol. 2005; 46: 2153–2167.[Abstract/Free Full Text]
  12. Yu CM, Lin H, Zhang Q, Sanderson JE. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration. Heart. 2003; 89: 54–60.[Abstract/Free Full Text]
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  14. Achilli A, Sassara M, Ficili S, Pontillo D, Achilli P, Alessi C, De Spirito S, Guerra R, Patruno N, Serra F. Long-term effectiveness of cardiac resynchronization therapy in patients with refractory heart failure and "narrow" QRS. J Am Coll Cardiol. 2003; 42: 2117–2124.[Abstract/Free Full Text]
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Response to Abraham and Abraham

Frits W. Prinzen, PhD; Angelo Auricchio, MD, PhD

We depart from opposite sides, but it appears that we and Drs Abraham and Abraham draw the same conclusions: QRS duration is not a perfect predictor of chronic resynchronization therapy (CRT) response, but echocardiographic techniques are not yet suitable to provide an improvement in this area. Although we agree on headlines, we would like to make a few additional comments. First, with recent studies showing the weakness of many mechanical variables, the poor correlation between QRS duration and mechanical dyssynchrony could well be due to the inaccuracy of determination of mechanical dyssynchrony measures. Indeed, several studies showed significant mechanical dyssynchrony even in healthy volunteers,1 which makes a proper definition of mechanical dyssynchrony questionable. Drs Abraham and Abraham also mentioned that reduction of QRS duration is not needed to achieve benefit of CRT. We agree with this opinion, but this observation cannot be used as an argument against baseline QRS duration as a selection criterion for CRT because the pathophysiology of this phenomenon is probably different.2 Second, speckle tracking–derived strain estimates appear to be more reliable measures (both theoretically and practically) than tissue Doppler imaging measures, but again, this approach also will require large-scale multicenter testing before it can be widely adopted. Furthermore, several studies indicate that even mechanical timing differences, determined with the use of magnetic resonance imaging tagging, do not provide a good prediction of CRT responders. Rather, indices containing the amount of strain appear to provide better predictions.3,4 Therefore, the novel techniques to measure strain offer interesting opportunities but by no means are ready for prime time. That is why we still recommend the use of QRS duration. Third, part of the argument for using mechanical dyssynchrony has come from single-center studies on CRT in patients with narrow QRS. After publication of the data on the Cardiac Resynchronization Therapy in Patients With Heart Failure and Narrow QRS (ReThinQ) study and presentation of data from the Evaluation of Screening Technologies in Electrically-Normal Mechanically-Dyssynchronous Heart Faiure Patients Receiving Cardiac Resynchronization Therapy (ESTEEM-CRT) study (Heart Rhythm Society, 2008), it is clear that at best only a subgroup of these patients may respond to CRT. However, another single-center study on CRT in patients with narrow QRS, not selected on the basis of echocardiographic criteria, reported good results similar to those observed in other studies using echocardiographic criteria.5 As stated by Drs Abraham and Abraham, we clearly need to better understand the mechanism of CRT. It may well be that some patients with narrow QRS respond to CRT but potentially through mechanisms other than dyssynchrony.


   Footnotes
 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

This is Part 2 of a 2-part article. Part 1 appears on page 70.


   References 
TOP
 Introduction
 Rationale for Evaluating...
 Limitations and Challenges of...
 Moving Forward After PROSPECT...
 References
 References 
 

  1. Conca C, Chinami M, Faletra FF, Oh J, Mantovani A, Hayes D, Klersy C, Sorgente A, Pasotti E, Pedrazzini GB, Moccetti T, Auricchio A. Range of normality of echocardiographic measures of mechanical synchony in healthy individuals: implication for a multiparametric approach in CRT patients. J Am Coll Cardiol. 2008; 51: A136. Abstract.
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