Circulation: Cardiovascular Imaging. 2008;1:70-78
doi: 10.1161/CIRCIMAGING.108.791772
Is echocardiographic assessment of dyssynchrony useful to select candidates for cardiac resynchronization therapy?
Echocardiography Is Not Useful Before Cardiac Resynchronization Therapy if QRS Duration Is Available
Frits W. Prinzen, PhD
and
Angelo Auricchio, MD, PhD
From the Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (F.W.P.); and Cardiocentro Ticino, Lugano, Switzerland (A.A.).
Correspondence to Frits W. Prinzen, PhD, Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. E-mail Frits.Prinzen{at}FYS.unimaas.nl
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Introduction
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Several multicenter prospective randomized trials have shown
that cardiac resynchronization therapy (CRT) improves functional
capacity and quality of life in
70% of symptomatic heart failure
(HF) patients.
1 A smaller proportion of these selected patients
shows a >5% increase in left ventricular (LV) ejection fraction
and a >15% reduction of LV end-systolic volume, indicating
reverse remodeling of the LV.
2 Finally, CRT reduces morbidity
and mortality rates by
30% to 40%.
3 These data are comparable
to those of established pharmacological therapies for HF, including
angiotensin-converting enzyme inhibitors, angiotensin receptor
blockers, β-blockers, and aldosterone antagonists. Of note,
CRT is indicated in HF patients who remained symptomatic despite
medical therapy; thus, they could be considered nonresponders
to medical therapy. However, the precise proportion of nonresponders
to medical therapy has not yet been quantified.
Response by Abraham and Abraham p 78
Notwithstanding CRT being a very efficacious and cost-effective treatment, several efforts have been made to reduce the number of nonresponder patients. The issue of patients not responding to CRT is rather complex. There is lack of agreement on the definition of nonresponder (volumetric, functional, or exercise response), the cause of CRT nonresponse is likely multifactorial, and some patients may be too sick to show a meaningful and measurable benefit ("beyond repair"). Currently, we do not know which factors are predicting response to therapy and the relative weight of each of these factors. Therefore, the proportion of patients who are not amenable to CRT remains undefined. Among the factors predicting response to CRT, the presence of mechanical dyssynchrony has been indicated to play a determinant role.4–7 The putative lack of responsiveness to CRT in the absence of mechanical dyssynchrony, together with evidence that mechanical dyssynchrony may exist even when QRS duration is within the normal range, has encouraged investigators to intensively study the hidden link between mechanical dyssynchrony and QRS duration (the latter being frequently but inappropriately indicated as electrical dyssynchrony).
Our task is to address the benefits of the use of the standard criteria for selection of patients for CRT as opposed to the (additional) use of imaging-derived indices of mechanical dyssynchrony. Arguments to adhere to currently available guidelines range from theoretical views on the mechanism of CRT to practical limitations of the techniques assessing mechanical dyssynchrony.
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The Mechanism of CRT
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In the current clinical practice of CRT, 2 pacing electrodes
(or a single LV electrode in combination with intrinsic activation)
create 2 wavefronts of activation.
8 This activation modality
is not physiological but is considerably better than the activation
during a left bundle-branch block (LBBB) (
Figure 1). This simple
concept is supported by data from electrical mapping and hemodynamics
in canine hearts with LBBB
9 and hemodynamic measurements in
patients.
10 Figure 1 also shows that biventricular pacing makes
activation more asynchronous than with normal physiological
activation. This is also the case in ventricles with an infarction
or diffuse slow conduction, conditions that may show mechanical
dyssynchrony (
Figure 1). However, the latter derangements are
likely not amenable to CRT.
11 Moreover, from the desynchronization
of normally activated ventricles by biventricular pacing, it
can be recognized that "nonresponse" in these cases of mechanical
dyssynchrony does not mean a neutral effect but rather worsening
cardiac pump function. Indeed, worsening pump function
12 and
increasing LV hypertrophy and sphericity
13 have been reported
in nonresponders. Therefore, proper prediction of CRT response
is important. Moreover, when poorly validated diagnostic tools
are used, there is a risk of creating more nonresponders, which
could lead to greater reservations against CRT and ultimately
even the withholding of this therapy from the patients who really
need and "deserve" it.
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Figure 1. Schematic representation of the sequence of electrical activation and contraction during baseline and during biventricular (BiV) pacing in the LV. From top to bottom, Normal, LBBB, infarction, and failure (with normal activation sequence). In normal electrical conduction, predominant sequence of activation is from endocardium to epicardium (arrows pointing outward). Contraction is indicated as arrows pointing inward, whereas paradoxical motion and stretching are indicated by arrows pointing outward. The RV and LV pacing electrodes are indicated by open and closed circles, respectively.
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QRS Duration, a Gross but Reliable Marker for CRT Patients
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The most recent guidelines on cardiac pacing and CRT issued
by the European Society of Cardiology/European Heart Rhythm
Association
14 have confirmed previous guidelines issued by other
scientific organizations
15 and do not recommend the use of mechanical
dyssynchrony as selection criteria for HF patients. Only a QRS
duration
120 ms is considered, among other criteria, an indication
for CRT. The European Society of Cardiology/European Heart Rhythm
Association Guidelines Writing Group, consisting of 12 scientists,
and the document reviewers, including 16 European experts in
the field of cardiac pacing and HF, stated in their recommendations
that "in spite of positive results from observational studies
of the benefit from CRT using mechanical dyssynchrony criteria
to select patients, the real value of the mechanical dyssynchrony
criteria for patient selection remains to be determined in randomized
studies.
14 A similar conclusion was drawn for CRT indication
in HF patients with QRS duration <120 ms. The rather conservative
view seems, however, to be reinforced by the recent results
of the Predictors of Response to CRT (PROSPECT) study
16 and
the CRT in Patients With Heart Failure and Narrow QRS (ReThinQ)
trial.
17 In analogy to LV ejection fraction, which is considered
a gross yet imperfect stratification risk marker for sudden
cardiac death but the best available thus far, QRS duration
represents a gross description of electrical and probably mechanical
(see below) ventricular asynchrony.
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Electrical Mapping
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We acknowledge the imperfect prediction of CRT response from
QRS duration. However, rather than being disappointed, one should
be surprised that such a simple and easy-to-measure index predicts
so well. Actually, it may be this easy assessment that makes
it such a strong tool in daily practice. A QRS prolongation,
even modest, indicates abnormal and inhomogeneous activation.
Increasing evidence suggests that LBBB, the most common ventricular
conduction disturbance in HF patients, is a heterogeneous conduction
disorder. High-resolution 3-dimensional mapping procedures showed
that the transseptal conduction time, ie, the time between the
earliest right ventricular (RV) and LV septal breakthrough point,
is bimodally distributed and has a large range in the group
of patients with transseptal conduction times >40 ms (
Figures 2 and 3
).
This indicates a large heterogeneity in the RV to LV activation
time. Furthermore, in patients with LBBB, the total LV endocardial
activation time ranges from 60 to 160 ms (
Figures 2 and 3).
Etiology does not seem to have a major impact on the total endocardial
activation time. Finally, the sum of transseptal and total endocardial
activation time does not account for the maximum duration of
the QRS; QRS duration is 20 to 60 ms longer, probably because
of LV endocardial to epicardial conduction time (
Figure 3).
These data also show that QRS duration provides a quite good
estimate of total electrical asynchrony.
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Figure 2. Left, Three-dimensional electroanatomic mapping of the RV and LV (left). A color-coded activation sequence indicates the earliest (red) and the latest (blue) endocardial activation region. The earliest activated region is the anterolateral region of the RV, and the latest part is the posterobasal region of the LV. TV indicates tricuspid valve. Right, Distribution of transseptal time and total endocardial activation time as measured by contact (CARTO) and noncontact (EnSite) mapping in 24 patients. Adapted from Auricchio et al18 with permission from the American Heart Association. Copyright 2004 American Heart Association.
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Figure 3. Distribution of transseptal time, total endocardial activation time, and total QRS duration in 140 HF patients with a QRS duration 120 ms. Patients are ordered according to QRS duration (A) and transseptal time (B).
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In addition, there is evidence that in LBBB the electrical activation
of the LV follows a "U-shaped" path, starting at the septum
and turning around the apex and subsequently toward the inferior
wall of the LV. This activation pattern is generated by a functional
line of block that is oriented from the base toward the apex
of the LV. The location and length of the lines of block are
highly variable but related to the site and time of LV breakthrough.
18 The U-shaped activation pattern has been confirmed by several
investigators using invasive noncontact mapping and noninvasive
body surface mapping techniques
18–21 (
Figure 4). The line
of block is predictably located in the anterior region of the
LV when the QRS duration is >150 ms.
18 Thus, there is a large
area of delayed electrical activation over the LV free wall,
where a lateral or posterolateral vein is usually found. This
fits the clinical observation that in this subset of CRT patients
the response is close to 90%.
20 In contrast, patients with QRS
duration <150 ms demonstrate a smaller line of block, more
frequently located in the lateral region of the LV. Therefore,
more precise characterization of the conduction patterns and
block regions in candidates for CRT may improve the response
rate to CRT. Such better characterization may help in choosing
the best site and mode of pacing (
Figure 5).
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Figure 4. Location of line of block in patients with ventricular conduction disturbance assessed with the use of noncontact mapping (left and middle) or noninvasive body surface mapping (right). Note the consistency in the anterior location of the line of block. QRSd indicates QRS duration. Adapted from Jia et al,19 Fung et al,20 and Lambiase et al 21 with permission from Elsevier (Ref. 19) and BMJ Publishing Group (Refs 20 and 21). Copyright 2008.
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Figure 5. Three-dimensional electroanatomic mapping in a patient with idiopathic dilated cardiomyopathy and LBBB. Note the large area (light blue to purple) of late activation (110 to 160 ms after earliest RV activation) over the LV free wall. The anatomic course of a single, long, and large vein (top left panel) is indicated by yellow dots. Changes in LV dP/dtmax at each pacing spot are indicated in the top right panel. A significant increase of LV dP/dtmax was observed over the entire freewall, but it peaked (3 time larger than baseline) when pacing was applied close to one of the most delayed regions (purple). QCA indicates quantitative coronary angiography; RAO, right anterior oblique; and LAO, left anterior oblique.
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Conflicting Evidence on the Relevance of Mechanical Dyssynchrony
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The aforementioned considerations in favor of the use of electrical
criteria for selecting CRT patients have been questioned by
a considerable number of relatively small, single-center studies,
which show a better response to CRT in the presence of mechanical
dyssynchrony.
4–7,22,23 However, these studies are opposed
by other studies showing no relation between mechanical dyssynchrony
and CRT response.
24–27 Moreover, preliminary data from
a recent prospective multicenter trial (PROSPECT) indicate that,
although some indices of dyssynchrony correlated with CRT response,
their sensitivity and specificity were fairly poor. It was concluded
that no single measure of mechanical dyssynchrony could be recommended
to further improve patient selection beyond the current guidelines.
16 These disappointing results were achieved despite specific training
on imaging methods for each of the 30 participating centers,
with a clear effort to enhance uniformity of approach. Furthermore,
there was marked variability in the analysis derived from the
identical images among the 3 blinded core centers.
A few single-center studies also indicated a predictive value for mechanical dyssynchrony in patients with narrow QRS complex.24,28,29 However, these results are contradicted by a multicenter, prospective randomized trial, the ReThinQ study. In the 172 enrolled patients with QRS duration <130 ms and mechanical dyssynchrony, 6 months of CRT did not provide significant improvement in peak oxygen consumption or ejection fraction or a reduction in LV volumes compared with a control group.17 Several factors, including prospective randomized design and the inclusion of a control group, may account for the difference with the small observational trials.
Collectively, these results showed that the use of mechanical dyssynchrony measured according to current criteria does not add significant value to QRS duration. This opinion is in agreement with a recent statement of an expert group of the American Society of Echocardiography.30
Theoretically, a proper mechanical index is relevant to the patient because ultimately it is pump function that matters. However, after concluding that the primary purpose of CRT is to correct conduction abnormalities, one should wonder what added value mechanical dyssynchrony can provide in addition to a good electrical index of intraventricular conduction block. Two points are of importance in this respect: (1) To what extent does mechanical behavior reflect electrical abnormalities? (2) What factors can confound the assessment of conduction abnormalities?
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What Additional Information Could Mechanical Dyssynchrony Provide?
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Electrical activation of myocytes is followed by their contraction,
the electromechanical delay being typically 30 to 50 ms. For
the LV as a whole, the electromechanical delay equals the delay
between the R wave on the ECG and the rise in LV pressure. Detailed
measurements in paced canine hearts have shown a close relationship
between electrical activation times and the time to onset of
fiber shortening.
31–34 In paced hearts, some regional
differences in electromechanical delay have been observed, but
these differences were 10 to 20 ms.
31 Such local differences
in electromechanical delay are an order of magnitude smaller
than required to explain significant mechanical dyssynchrony
in the presence of a narrow QRS complex or the absence of mechanical
dyssynchrony in the presence of a wide QRS complex. Even when
one accounts for the well-known abnormalities in excitation–contraction
coupling in failing hearts, it is highly questionable whether
regional differences in electromechanical delay on the order
of 100 ms can occur. Therefore, one should consider that discrepancies
between electrical and mechanical dyssynchrony are due to confounding
factors. One such factor could be myocardial ischemia or infarction.
Ischemic, stunned, hibernating, and infarcted tissue is almost
entirely passive. Accordingly, it is being stretched by adjacent
contracting fibers and the rise in LV cavity pressure (
Figure 1).
This region subsequently "shortens" during late systole, when
LV pressure is falling again. Indeed, in some of the earliest
reports on mechanical dyssynchrony in patients with narrow QRS
complex, such dyssynchrony is reported in patients with ischemic
cardiomyopathy.
22 Such mechanical behavior provides the impression
of a "late contracting" region, but in reality this is simply
reversal of the LV pressure–induced ballooning of the
passive tissue. As discussed in more detail elsewhere, such
tissue is clearly not amenable to CRT.
11 A similar impression
of mechanical dyssynchrony can arise as a consequence of specific
events like cardiac surgery.
35
Another confounding factor for mechanical dyssynchrony may be the increased inhomogeneity of regional contraction in failing ventricles, as observed with the conductance catheter technique36 and magnetic resonance imaging–derived radial wall motion analysis,37 even in ventricles with narrow QRS complexes. Valve surgery resolved these abnormalities in cases of valvular disease,36 suggesting that in these failing hearts mechanical overload generates dispersion of contraction. It is unlikely that such dispersedly distributed contraction is amenable to CRT (Figure 1). Therefore, when a good electrical index of dyssynchrony is available, the additive value of assessment of mechanical dyssynchrony is highly questionable.
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Issues With Regard to Measurement of Mechanical Dyssynchrony
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In addition to the aforementioned factors, imperfect measurement
techniques and analyses may contribute to the inconsistent relation
between mechanical dyssynchrony and CRT response. Extensive
review of imaging techniques is beyond the scope of this article
and can be found elsewhere.
5,30,38 Briefly, measures of mechanical
dyssynchrony may be based on timing of valve opening or on displacement,
velocity, or deformation (strain) of tissue (
Figure 6). Indices
correlating best with local tissue behavior are those derived
from local strain because motion or velocity with respect to
an external reference point is confounded by factors like rigid
body motion and behavior of adjacent regions (
Figure 6).
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Figure 6. Principles of measurement of myocardial displacement, velocity, strain rate, and strain with the use of ultrasound (US) techniques. TDI measures velocities of the tissue with respect to the ultrasound probe. Local velocity depends on rigid body motion and rotation of the ventricle (gray arrows) and local shortening (black arrows), whereas only the latter reflects local mechanical behavior of the tissue. Adapted from http://folk.ntnu.no/stoylen/strainrate/Ultrasound/index.html#section_index with permission from Dr Asbjørn Støylen, ©2008.
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It should be realized that deformations in the asynchronous
heart are characterized by the most complicated patterns known
32,39 (
Figure 7); a simplified and partly flawed analysis of such
complex motion pattern can easily lead to inconsistent data
(
Figure 6). Inappropriate alignment of the ultrasound beam with
respect to the LV wall, as is frequently the case when velocities
in the basal LV segments are analyzed, causes major deviations
of the timing of onset and peak shortening.
27 In that respect,
it is surprising that it is advised to measure velocities at
the most basal part of the LV wall because in that area the
wall bends inward, and consequently the ultrasound beam is at
a large angle with the wall. Velocity tracings can also change
considerably by even slight changes in the position of the sample
volume.
27 The latter can be understood if one considers that
myocardial deformation is a complex 3-dimensional process with
different amounts and timing of shortening in different directions.
40
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Figure 7. Example of TDI and 2-dimensional (2D) strain measurements (speckle tracking) in a patient with dilated cardiomyopathy. TDI measurement indicated no mechanical dyssynchrony, whereas strain measurement showed dyssynchrony between the septum (upper) and lateral wall (lower trace). MVC indicates mitral valve closure; AVO, aortic valve opening; MVO, mitral valve opening; AVC, aortic valve closure. Courtesy of Dr DeBoeck, Department of Cardiology, University Medical Center, Utrecht, The Netherlands.
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The observation that the degree of ventricular dyssynchrony
obtained by measuring the septal-to-lateral delay was similar
in patients with and without scars
41 emphasizes the intrinsic
limitation of tissue Doppler imaging (TDI) in distinguishing
whether a segment is actively contracting or whether it moves
passively as a result of active contraction in neighboring segments.
42 An additional limitation of this method is indicated by the
fact that a delayed contraction of the lateral wall was found
in only
66% of the patients with LBBB
27 and that CRT did not
show a significant decrease in mechanical dyssynchrony.
27,43 Finally, multiple peaks during TDI examinations are frequently
observed and may create inconsistent choices for which peak
in the TDI signal should be chosen as peak systolic velocity
even by experienced operators
27; this may explain the considerable
interobserver and intraobserver variability in the PROSPECT
trial.
16 Therefore, it seems that many mechanical dyssynchrony
measures suffer from technical limitations of the technology
and from difficult interpretation of the complex signals.
The technical limitations may, however, not be the only reason for the poor relation between CRT response and mechanical dyssynchrony. Two studies using MRI tagging, the gold standard on local deformation measurements, also showed a poor relation between indices of mechanical dyssynchrony and CRT response.44,45 In one of the studies, QRS duration was even a better predictor of CRT response.44 However, the use of indices related to discoordination (amount of stretch during systole) improved the prediction of CRT response. Therefore, it is possible that we need to focus more on discoordination, which is facilitated by the recent availability of speckle-tracking analysis.46
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Conclusions
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Strong evidence indicates that QRS duration reflects conduction
abnormalities, the details of which could be even better assessed
with novel electrical mapping techniques. The "epidemic of mechanical
dyssynchrony" in HF patients, as recently discussed by Kass,
11 clearly suggests that current conventional echocardiographic
assessment techniques are imperfect, inaccurate, or not used
properly. Alternatively, apparent mechanical dyssynchrony may
be due to abnormalities other than those that can be treated
with CRT. In either case, we deeply appreciate and share a recent
expert consensus statement of the American Society of Echocardiography,
as follows: "Although a number of echocardiographic dyssynchrony
methods have suggested superiority to ECG QRS width for predicting
response to CRT, ... this writing group currently does not recommend
that patients who meet accepted criteria for CRT should have
therapy withheld because of results of an echocardiographic
Doppler dyssynchrony study."
30 Dr Theodore P. Abraham is one
of the authors of this statement.
Thus, there is very strong evidence for continued application of the current guidelines, with the use of simple ECG criteria, for selection of CRT patients. We acknowledge that additional information on structural and mechanical information may be of great value for increasing the proportion of clinical and/or volumetric response to CRT, but a reliable measure for this purpose has yet to be developed. Novel electroanatomic methods may be of help as much as novel mechanical measures.
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Acknowledgments
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Disclosures
Dr Prinzen has received research grants from Medtronic, Boston Scientific, and EBR Systems and served as a consultant for Medtronic Inc and Boston Scientific. Dr Auricchio received research grants from Medtronic, Boston Scientific, and St Jude Medical; received honoraria from Biotronik, Sorin, and Medtronic; and served as a consultant for Sorin.
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Response to Prinzen and Aurrichio
Jacob Abraham, MD; Theodore P. Abraham, MD
Drs Prinzen and Aurrichio "acknowledge the imperfect prediction of CRT response from QRS duration," and we enthusiastically concur with their opinion. Evidence at the experimental and clinical level suggests an electrical–mechanical disconnect. Therefore, it is reasonable to assume that QRS alone is not an accurate indicator of mechanical dyssynchrony. We submit that a necessary component for response to chronic resynchronization therapy (CRT) is mechanical and not electrical dyssynchrony. Indeed, it is not the electrical conduction delay per se but the associated mechanical dyssynchrony that results in inefficient ventricular contraction and reduced stroke volume. Consequently it makes sense that correcting the mechanical dyssynchrony via CRT leads to morphological, functional, and clinical improvements. Furthermore, we would like to offer our thoughts on some of the opinions expressed by Drs Prinzen and Aurrichio. First, their concern that significant regional differences in electromechanical delay cannot exist with a narrow QRS should be allayed by data showing quantitatively similar delays in LV free wall activation between patients with narrow QRS and left bundle-branch block heart failure, albeit in a minority of the patients with narrow QRS.1 Second, they imply that discordance between mechanical and electrical dyssynchrony indices can be explained away by "confounding factors." Evidence to the contrary comes from a canine dyssynchronous heart failure model in which preexcitation of the LV free wall can bring about improvement in hemodynamics and mechanical coordination despite worsening of electrical dispersion.2 Third, they conclude that there is a poor correlation between indices of mechanical dyssynchrony and CRT response. We suggest that the issue of poor correlation pertains more to the particular technique rather than the concept. We agree that current tissue Doppler and similar echocardiographic techniques may not be well developed for dyssynchrony analysis at the current time. Moreover, it is our opinion that all echocardiography-based dyssynchrony analysis should be revisited with thoughtful and rigorous protocols. We contend that positive publication bias and general unawareness of the shortfalls of the echo-based techniques have led to the current uncertainty of their potential role in CRT. However, we maintain that the fundamental concept proposed by these echo-based techniques is valid and has been corroborated by other techniques. For example, magnetic resonance demonstrates a strong correlation between mechanical dyssynchrony and improvements in both systolic and diastolic function.3 Finally, it is our opinion that mechanical dyssynchrony will be one of multiple factors, including etiology, that will determine response to CRT. We submit that not offering CRT to a patient on the basis of the absence of mechanical dyssynchrony by echocardiography may not be optimal given the variability and conflicting data. However, corroboration of mechanical dyssynchrony by any technique, especially in borderline cases, may help with making a clinical decision. However, technical challenges persist and should be duly acknowledged and taken into account while adjudicating on individual cases.
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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.
This is part 1 of a 2-part article. Part 2 appears on page 79.
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References
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- Turner MS, Bleasdale RA, Vinereanu D, Mumford CE, Paul V, Fraser AG, Frenneaux MP. Electrical and mechanical components of dyssynchrony in heart failure patients with normal QRS duration and left bundle-branch block: impact of left and biventricular pacing. Circulation. 2004; 109: 2544–2549.[Abstract/Free Full Text]
- Leclercq C, Faris O, Tunin R, Johnson J, Kato R, Evans F, Spinelli J, Halperin H, McVeigh E, Kass DA. Systolic improvement and mechanical resynchronization does not require electrical synchrony in the dilated failing heart with left bundle-branch block. Circulation. 2002; 106: 1760–1763.[Abstract/Free Full Text]
- Helm RH, Leclercq C, Faris OP, Ozturk C, McVeigh E, Lardo AC, Kass DA. Cardiac dyssynchrony analysis using circumferential versus longitudinal strain: implications for assessing cardiac resynchronization. Circulation. 2005; 111: 2760–2767.[Abstract/Free Full Text]
TOP
Introduction
The Mechanism of CRT