doi: 10.1161/CIRCIMAGING.108.791772
Controversies in Imaging |
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
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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 Top Introduction The Mechanism of CRTQRS Duration, a Gross...Electrical MappingConflicting Evidence on the...What Additional Information...Issues With Regard to...ConclusionsReferencesReferences |
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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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TopIntroductionThe Mechanism of CRTQRS Duration, a Gross...Electrical MappingConflicting Evidence on the...What Additional Information...Issues With Regard to...ConclusionsReferencesReferences |
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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 LBBB9 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 function12 and increasing LV hypertrophy and sphericity13 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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QRS Duration, a Gross but Reliable Marker for CRT Patients |
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TopIntroductionThe Mechanism of CRTQRS Duration, a Gross...Electrical MappingConflicting Evidence on the...What Additional Information...Issues With Regard to...ConclusionsReferencesReferences |
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The most recent guidelines on cardiac pacing and CRT issued by the European Society of Cardiology/European Heart Rhythm Association14 have confirmed previous guidelines issued by other scientific organizations15 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) study16 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. |
Electrical Mapping |
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TopIntroductionThe Mechanism of CRTQRS Duration, a Gross...Electrical MappingConflicting Evidence on the...What Additional Information...Issues With Regard to...ConclusionsReferencesReferences |
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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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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 techniques18–21 (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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Conflicting Evidence on the Relevance of Mechanical Dyssynchrony |
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TopIntroductionThe Mechanism of CRTQRS Duration, a Gross...Electrical MappingConflicting Evidence on the...What Additional Information...Issues With Regard to...ConclusionsReferencesReferences |
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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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TopIntroductionThe Mechanism of CRTQRS Duration, a Gross...Electrical MappingConflicting Evidence on the...What Additional Information...Issues With Regard to...ConclusionsReferencesReferences |
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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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TopIntroductionThe Mechanism of CRTQRS Duration, a Gross...Electrical MappingConflicting Evidence on the...What Additional Information...Issues With Regard to...ConclusionsReferencesReferences |
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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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It should be realized that deformations in the asynchronous heart are characterized by the most complicated patterns known32,39 (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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The observation that the degree of ventricular dyssynchrony obtained by measuring the septal-to-lateral delay was similar in patients with and without scars41 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 LBBB27 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 operators27; 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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TopIntroductionThe Mechanism of CRTQRS Duration, a Gross...Electrical MappingConflicting Evidence on the...What Additional Information...Issues With Regard to...ConclusionsReferencesReferences |
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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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References |
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44. Rüssel IK, Zwanenburg JJ, Germans T, Marcus JT, Allaart CP, de Cock CC, Götte MJ, van Rossum AC. Mechanical dyssynchrony or myocardial shortening as MRI predictor of response to biventricular pacing? J Magn Reson Imaging. 2007; 26: 1452–1460.[CrossRef][Medline]
45. Kirn B, Jansen A, Bracke F, Van Gelder B, Arts T, Prinzen FW. Mechanical discoordination rather than dyssynchrony predicts reverse remodelling upon cardiac resynchronization [published online before print May 30, 2008]. Am J Physiol Heart Circ Physiol.
46. Suffoletto MS, Dohi K, Cannesson M, Saba S, Gorcsan J III. Novel speckle-tracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation. 2006; 113: 960–968.
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.
Response to Prinzen and Aurrichio
Jacob Abraham, MD; Theodore P. Abraham, MD
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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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TopIntroductionThe Mechanism of CRTQRS Duration, a Gross...Electrical MappingConflicting Evidence on the...What Additional Information...Issues With Regard to...ConclusionsReferencesReferences |
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1. 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.
2. 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.
3. 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.
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