Controversies in Imaging |
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 |
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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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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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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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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 |
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Sources of Funding
This work was supported in part by grants from the National Institutes of Health (AG22554 and HL076513).
Disclosures
None.
| References |
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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 |
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This is Part 2 of a 2-part article. Part 1 appears on page 70.
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