doi: 10.1161/CIRCULATIONAHA.107.728748
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(Circulation. 2007;116:1434-1436.)
© 2007 American Heart Association, Inc.
Editorial |
Highlighting the R in CRT
From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
Correspondence to Dr David A. Kass, Division of Cardiology, Ross 835, Johns Hopkins Medical Institutions, 720 Rutland Ave, Baltimore, MD 21205. E-mail dkass{at}jhmi.edu
Key Words: Editorials • heart failure • pacing • remodeling • Doppler imaging • electrical stimulation
Treatment of congestive heart failure by artificial pacing first attracted attention in the early 1990s when reports showed that standard right ventricular apical pacing with a shortened atrioventricular delay improved heart function in a subgroup of patients.1 However, few seemed to benefit from this approach,2 whereas by altering the pacing site to the left ventricle and using biventricular stimulation in patients with intramyocardial conduction delay, one achieved more consistent functional improvement.3,4 The short-term response was greater in patients with a wider QRS complex, typically a left bundle branch pattern,5 and subsequent clinical trials that showed biventricular pacing improved morbidity6,7 and mortality8 principally selected only those patients with a prolonged QRS duration.
Article p 1440
However, the story was never that straightforward, as investigators found that the correlation between basal QRS duration and immediate mechanical responses to biventricular pacing was poor5 and not predictive of long-term outcome.9 QRS narrowing after cardiac resynchronization therapy (CRT) was not useful either.10,11 Furthermore, patients with a narrow QRS but mechanical dyssynchrony also benefited from CRT. This situation posed a problem because it was clear from the outset that identification of the right patients was important given the invasive nature and expense of CRT. In an early attempt to predict short-term response, we found mechanical dyssynchrony (assessed with magnetic resonance imaging) or the combination of QRS duration with functional data (basal dP/dtmax) better predicted short-term responders.5 Shortly after, echo-Doppler imaging methods were developed to assess dyssynchrony, and multiple groups found that these methods better predicted long-term CRT response.9,12–14 Just what constituted a CRT response had to be defined and varied from an end-systolic volume (ESV)13 reduction or increased ejection fraction12 to clinical improvement.14
One might think the plot would end here; every CRT candidate is tested for mechanical dyssynchrony, and if it is present at some predetermined threshold they receive therapy with a >90% chance of responding: not a bad situation. However, reality has been more complex, and even with all the dyssynchrony metrics in use, nonresponsive patients remain plentiful. Perhaps the problem lies less with identifying dyssynchrony and more with being sure the therapy actually improved it. In the current issue of Circulation, Bleeker et al15 examined this hypothesis. The investigators followed a group of 100 patients, all with class III–IV dilated heart failure, a mean QRS duration of 168 ms, and left ventricular dyssynchrony (maximal time delay between peak systolic tissue velocities in the left ventricle) of >65 ms (mean, 114 ms). CRT immediately improved dyssynchrony in most subjects, and the magnitude of resynchronization remained virtually identical after 6 months of CRT. The authors defined responders as those with a 
10% decline in ESV because this was found in a prior study to better predict survival in CRT patients than did clinical symptoms.16 Of the 15% of patients who did not respond over the long term, resynchronization from CRT was borderline (P=0.08) and approximately one third the magnitude of that in responders. Furthermore, patients without at least a 20% improvement in dyssynchrony did not respond long term to CRT. The primary conclusion was that you need to have some CR if you are going to benefit from CRT.
The present study by Bleeker et al raises a number of interesting issues. First, the percentage of responding patients defined by a reduced ESV was 85%, higher than the 
65% rate often reported. Indeed, with the use of more liberal criteria (>15% decline in ESV), this same group17 and others18,19 previously reported 55% to 65% response rates. Furthermore, the magnitude of ESV decline was 30%, 2 to 3 times the average change reported in prior CRT studies.14,20,21 One difference is that patients in the present trial had to have both a long QRS and basal dyssynchrony (>65 ms delay by tissue Doppler imaging), whereas prior studies only used a long QRS duration as the criterion. This supports the notion that subjects with both electrical and mechanical evidence of intraventricular delay are the most likely to respond to CRT.
What about the actual relationship between resynchronizing the left ventricle and observing a long-term decline in ESV—is the former mandatory as claimed? Perhaps it is, though the magnitude of one does not appear to be very predictive of the magnitude of the other. Although an overall correlation existed between the reduction of mechanical dyssynchrony and long-term lowering of ESV (Figure 4 in the article by Bleeker et al15), this was driven by the patients with 
30% change in synchronization. For the nearly 90% of patients with change above this level, the results were widely scattered with minimal correlation between variables. Approximately 10 patients fell at or just above the 10% 
ESV cut-off yet had impressive resynchronization. So, although mechanical resynchronization may indeed be required to reverse chronic chamber dilation (ie, reduces ESV), it is not necessarily sufficient. Another issue is that this graph depicts percentage changes, and >80% reduction of dyssynchrony in an individual with a marked basal delay likely means something quite different than in an individual whose basal dyssynchrony was much less.
Another important factor is how one defines a responder. The choice of a 10% decline in ESV was based on a recent study of 141 dilated heart failure patients with QRS >120 ms who received CRT.16 After receiver-operator curve analysis, the authors found that a 9.5% decline in ESV provided the best sensitivity and specificity for all-cause (70% for both) and cardiovascular (89% and 67%, respectively) mortality. This was more predictive than clinical symptoms. However, the latter are ultimately what patients and their doctors must confront, and improvement of symptoms is arguably a primary goal for heart failure treatment. We do not know how the current analysis would look if a clinical end point had been chosen. The 10% ESV range is similar to that achieved by other therapies that improve mortality, such as ß-blockers and angiotensin inhibitors.22 However, this numeric cut-off is not so black and white, and the presence of another 10% of patients at or just above this cut-off in the present study suggests that fewer clinical responders than presumed may exist even in this group. If so, this would be interesting because it suggests that, even with evidence of mechanical resynchronization, additional complexities exist that ultimately determine how well a patient responds to CRT. These complexities could include the underlying myocardial disease, severity of molecular abnormalities, excitation-contraction coupling, loss of viable myocytes, arrhythmogenicity, fibrosis and/or scar tissue, and other factors.
Although the findings from Bleeker et al15 support the reduction of mechanical dyssynchrony as a key target for long-term CRT benefit, this reduction is less directly applicable to the identification of candidates because patients must already be treated by CRT to reveal the resynchronization effect. In earlier work, Bax et al14 reported that simply by use of a tissue Doppler imaging delay of >65 ms (required for inclusion in the present study), one achieved a 92% sensitivity and specificity for prediction of >15% long-term decline in ESV. On the basis of this finding, all but 8% of the subjects in the present study should have had at least a 15% decline in ESV, yet, as seen in Figure 4, 30% fell below this range. This highlights the continued need for larger, prospective, multicenter, blinded analyses that use several proposed dyssynchrony indexes to determine their ultimate predictive value for CRT outcome. Use of the <20% change in dyssynchrony threshold in the present study15 improved the negative predictive accuracy to 100%, yet, as noted, this result depended on the exact ESV threshold used to distinguish responders from nonresponders. One could argue that the results support more efforts to assess mechanical changes during lead implantation itself with the use of an external stimulator to test the effects. Lack of any demonstrable resynchronization effect despite various left ventricular lead positions would be a criterion not to implant. Efforts have been made to assess regional motion during implantation itself, but this assessment is difficult. New technologies may provide surrogate wall motion signals, but these remain under development. Global hemodynamic surrogates such as arterial pulse pressure change, which reflects, in the short term, improved cardiac output,4 or change in dP/dtmax have also been explored to a limited degree. Change in dP/dtmax with CRT correlates with basal values and with the severity of dyssynchrony,5,10,23 and perhaps the combination of this measure with electrical and wall timing parameters can improve a predictive index.23 An ability to vary the left ventricular stimulation site and thus modify implementation would be desirable to make full use of such information.
Finally, the present results pose an interesting contrast to pharmacological treatments for heart failure, where short-term changes have rarely been predictive of long-term efficacy. The prime example is ß-blockade, where short-term effects are directionally opposite to those observed over the long term. Although some investigators have made a broad conclusion that short-term responses can never predict treatment efficacy because the disease is simply too complex, the experience with CRT suggests that this may have more to do with what is being targeted. As shown early on, the impact of CRT on resynchronization is immediate, within a single beat, and is achieved by its direct modulation of wall motion timing and mechanics.5 Although other changes such as reduction of chamber size and exertional improvement undoubtedly involve a more complex interplay between this direct effect and the underlying heart failure pathophysiology, if you do not achieve the first part then it seems very unlikely that you will achieve the second. The present study highlights this and should further efforts to identify optimal candidates. We have a good idea of what we can achieve in the short term, and the new evidence that this effect changes little over time yet predicts long-term remodeling15 is reassuring. We still need to better standardize measurements of dyssynchrony, make them as objective and reproducible as possible, and consider them in the context of electrical and global mechanical behavior to improve their predictive accuracy. If we can do this, we should be able to improve CRT patient selection.
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Acknowledgments |
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Dr Kass is supported by PO1HL077180, the Belfer Laboratory for Heart Failure Research, and the Abraham and Virginia Weiss Professorship.
Disclosures
Dr Kass has served as a consultant for Boston Scientific.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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