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European Heart Journal Advance Access published online on November 11, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn481
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Toward understanding response to cardiac resynchronization therapy: left ventricular dyssynchrony is only one of multiple mechanisms

Chirine Parsai1,*, Bart Bijnens1,2,3, George Ross Sutherland1, Aigul Baltabaeva1, Piet Claus2, Maciej Marciniak1, Vince Paul1, Mike Scheffer4, Erwan Donal5, Geneviève Derumeaux6 and Lisa Anderson1

1 Department of Cardiology, St George’s Hospital, Blackshaw Road, SW17 0QT London, UK
2 ICREA, Universitat Pompeu Fabra (CISTIB), Barcelona, Spain
3 University of Leuven, Belgium
4 Medical Centre Rijnmond South, Rotterdam, The Netherlands
5 Hopital Pontchaillou, Rennes, France
6 Hopital Louis Pradel, Lyon, France

Received 16 April 2008; revised 2 September 2008; accepted 2 October 2008.

* Corresponding author. Tel: +44 2087251397, Fax: +44 2087254402, Email: chirineparsai{at}hotmail.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 References
 
Aim: To date, most published echocardiographic methods have assessed left ventricular (LV) dyssynchrony (DYS) alone as a predictor for response to cardiac resynchronization therapy (CRT). We hypothesized that the response is instead dictated by multiple correctable factors.

Methods and results: A total of 161 patients (66 ± 10 years, EF 24 ± 6%, QRS > 120 ms) were investigated pre- and post-CRT (median of 6 months). Reduction in NYHA Class ≥1 or LV reverse remodelling (end-systolic volume reduction ≥ 10%) defined response. Four different pathological mechanisms were identified. Group1: LVDYS characterized by a pre-ejection septal flash (SF) (87 patients, 54%). Elimination of SF (77 of 87 patients) resulted in reverse remodelling in 100%. Group 2: short-AV delay (21 patients, 13%) resolution (19 of 21 patients) resulted in reverse remodelling in 16 of 19. Group 3: long-AV delay (16 patients, 10%) resolution (14 of 16 patients) resulted in NYHA Class reduction ≥1 in 11 with reverse remodelling in five patients. Group 4: exaggerated LV–RV interaction (15 patients, 9%) reduced post-CRT. All responded clinically with fall in pulmonary artery pressure (P = 0.003) but did not volume respond. Group 5: patients with none of the above correctable mechanisms (22 patients, 14%). None responded to CRT.

Conclusion: CRT response is dictated by correction of multiple independent mechanisms of which LVDYS is only one. Long-axis DYS measurements alone failed to detect 40% of responders.

Key Words: Echocardiography • Heart failure • Cardiac resynchronization therapy


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Funding
 References
 
With the aim of better selecting patients for cardiac resynchronization therapy (CRT), the echocardiographic timing of long-axis regional systolic events (velocities, displacement, and deformation) has been employed to evaluate left ventricular (LV) dyssynchrony (DYS).1–7 However, this approach is often technically difficult in the clinical setting in a population of patients with globular, thin-walled ventricles in whom long-axis displacement is reduced and may approach the noise level of the ultrasound system. Radial DYS—less dependant on overall cardiac rotational displacement, using either M-mode8,9 or strain imaging6,10—has been investigated but was found to be unreliable in patients with previous septal infarction.11,12

In this study, we hypothesize that the response to CRT is governed by multiple independent mechanisms easily detectable echocardiographically, of which LVDYS is only one. A better approach would therefore be to identify all the underlying mechanisms potentially amenable to CRT in order both to determine the most likely responders and also to comprehend and potentially address non-response to therapy.

Additionally, as the current long-axis approach to identifying LVDYS presents technical limitations inherent in imaging failing hearts, an approach based on radial motion would help to distinguish the direct mechanical consequences of LBBB-induced electro-mechanical coupling in the impaired LV [septal flash (SF)—see Methods].

Defining a response to CRT is increasingly recognized as a key and complex issue—possibly indicating a spectrum of response rather than an absolute threshold differentiating responders and non-responders. In order to reflect this, we employed both clinical and echocardiographic outcome measures.13


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Funding
 References
 
Patient population
As part of a prospective study into the mechanisms underlying successful response to CRT, we assessed 161 patients (129 men and 32 women, aged 66 ± 10 years), from four centres [St George’s Hospital, London, UK (57 patients) Hopital Louis Pradel, Lyon, France (44 patients), CHU de Pontchaillou, Rennes, France (46 patients), Medical Centre Rijnmond South, Rotterdam, The Netherlands (14 patients), undergoing CRT as part of their clinical management in line with the current international guidelines (EF<35%, QRS duration > 120 ms, NYHA Class III–IV and under optimal pharmacotherapy)].14 Patients were recruited during hospital admission or following attendance to outpatient appointments and those whose condition might improve from coronary revascularization or valve replacement were excluded. The study complied with the declaration of Helsinki was approved by the Local Ethics Committees, and informed consent was obtained from each participant. Among London cohort’s patients, 15 were dropped from recruitment, six of which were excluded due to an improvement in LV function under medical therapy, six refused further follow-up after CRT, and two patients died before having CRT. All of the remaining could be followed-up. In the other centres, no patient had to be excluded after the initial assessment or refused to give consent. Device optimization (iterative method) was performed at a median of 1 (1–1.6) months. Clinical and echocardiographic evaluations were performed at baseline prior to CRT and at a median of 6 months (3–6).

Definition of response
Reverse remodelling was defined as a reduction of end-systolic volume (LVESV) ≥10%.15 Clinical response was defined as a reduction in NYHA Class ≥1,16 and was assessed by clinicians blinded to echocardiographic results in all cases. Serial plasma NT pro-BNP measurements were additionally performed in the London cohort prior and after CRT (at 1, 3, and 6 months).

Echocardiographic acquisition
A complete standard transthoracic ultrasound examination was performed by an imaging cardiologist in each centre. This included the acquisition of complete grey scale imaging datasets and both colour and spectral Doppler flows as well as myocardial velocity data (GE Vivid 7 scanner). For each acquisition, three heart cycles were stored for post-processing (EchoPac, GE). The full dataset was then analysed by a single investigator (C.P.).

LV internal dimensions in end-diastole (LVEDD) and end-systole (LVESD) were measured on parasternal long-axis (PLAX) M-mode images. LV volumes and ejection fraction (LVEF) were measured using the 2D Simpson method. Transmitral flow velocities were obtained from the apical-4-chamber (4-CH) view using pulsed-wave Doppler positioned at the tip of the leaflets. Peak E-wave, its deceleration time and A-wave velocities were measured. Mitral regurgitation (MR) and the presence of pre-systolic MR were assessed in the standard manner.

Doppler myocardial imaging velocity data were recorded using a narrow sector and optimal depth of imaging (frame rates of 200–300 Hz), using apical (long-axis motion) and short-axis (SAX) (radial motion) views as previously described.17 The velocity range setting was adjusted in order to avoid aliasing, still maximizing velocity resolution. End-diastole (onset of isovolumic contraction) and end-systole (aortic valve closure) were determined using transmitral and aortic Doppler profiles.

Mechanism-based approach for predicting response
We hypothesized that the presence of any of the following mechanisms on the pre-CRT echocardiographic assessment would predict potential for improvement after CRT.

Patients were thus sub-divided in the following subgroups: intra-ventricular DYS, atrio-ventricular (AV) DYS with either a short-AV (FILLINGshort) or a long-AV delay (FILLINGlong), inter-ventricular DYS with abnormal LV–RV interaction (L–R interaction) (see Results).

Septal flash method
We hypothesized that the direct mechanical consequence of dyssynchronous contraction induced by LBBB can be identified by detecting the early activation of the septum (IVS) as demonstrated in earlier animal experiments.18–20 We therefore assessed patients for the following echocardiographic findings:

  1. The presence of an early septal thickening/thinning (SF) within the isovolumic contraction period. The SF could be visualized on the SAX or PLAX either using grey scale (Figure 1) or Tissue Doppler colour M-mode (CMM) (see rapid change of colour related to the early and fast contraction of the septum occurring during the isovolumic period in Figure 2). The presence of this fast early septal shortening/lengthening could be confirmed also on a transverse CMM obtained using an apical-4-CH view. Basal, mid, and apical segments of the septum were checked for the presence of a SF.
  2. The timing and extent of SF was measured by the amplitude of early radial septal velocities. The velocity profiles of septal vs. inferolateral wall were also compared (normal LV, mirrored; LVDYS, non-mirrored or parallel; Figure 3).


Figure 1
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  		Figure 1 Septal flash identified on two-dimensional grey scale images. The inward motion of the right and left ventricular occurs after the septal flash indicating that it is not the result of a right–left ventricular interaction.

 

Figure 2
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  		Figure 2 Overview of the echocardiographic appearance of the four different subgroups that might respond to cardiac resynchronization therapy. In dyssynchrony (top left), the septum shows an early and fast thickening and thinning in the isovolumic contraction time period (septal flash on the colour M-mode), which is reverted by the thickening of the lateral wall. Short- and long-AV delays are identified from the transmitral flow (right) and right–left ventricular interaction with passive motion of the septum (bottom left).

 

Figure 3
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  		Figure 3 Radial velocities from the septum and infero-lateral wall. In normals (left), the velocities patterns appear mirrored from the onset of QRS to the onset of early filling. In patients (middle) with septal flash, the septum moves abnormally fast inward after the onset of QRS, immediately followed by outward motion when the opposite wall starts to move inward. Successful cardiac resynchronization therapy normalizes the velocities (right). Q-O, indicates onset of QRS; AVO, aortic valve opening; AVC, aortic valve closure.

 
Assessment of dyssynchrony
Described methods for assessing LVDYS
We compared our findings with the two most frequently described methods to detect intra-ventricular DYS:
  • We calculated Ts-SD12—that is the standard deviation of time from QRS to peak systolic velocity measured in 12 segments (a cut-off value ≥32.6 ms has been reported to predict response to CRT).21
  • We also used four segments DYS (DI4)—that is the maximal delay between onset of QRS to peak systolic velocity measured in four basal segments.1 A cut-off value of ≥65 ms has been reported to predict response.
The inter-ventricular delay (IVD) was calculated as the difference between the LV (LVPEP) and RV (RVPEP) pre-ejection periods, measured from QRS to onset of pulmonary and aortic flows, respectively.3

Statistics
Statview 5.0 (SAS institute Inc.) was used for statistical analysis. Normally distributed continuous variables were expressed as means ± standard deviation or median and (interquartile) range when large deviations of the Gaussian distribution were noticed. Sensitivity, specificity, positive, and negative predictive values were estimated with their 95% confidence intervals (95% CI). Continuous variables within and between groups were compared using two-sided paired and unpaired Student’s t-test. An inflation of the experiment wise type I error was not expected, as values were tested once within a subgroup comparing baseline and follow-up values. Categorical data for MR were compared using the Cochran–Armitage test for trends. A two-tailed P-value < 0.05 was considered statistically significant. As no single sample size calculation based on the test reproducibilities of a single measurement could be made, the sample size was based essentially on the sample size used in previously published work on the same topic at the time of submission.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Funding
 References
 
Baseline Clinical and Echocardiographic Indices
The baseline characteristics of all patients are summarized in Table 1. There were no significant clinical differences at baseline. At baseline, Ts-SD12 and DI4 were not significantly different in responders (clinical or volume responders) and non-responders. Responders had in average significantly more pronounced inter-ventricular DYS at baseline [43 (24–63) ms vs. 24 (19–36) ms, P = 0.02]. Abnormal LV filling was more frequent among responders.


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  		Table 1 Baseline characteristics: comparison between responders and non-responders

 
Patient subgroups
According to baseline measurements, we divided the 161 patients into five subgroups each representing the assumed underlying mechanism contributing to heart failure (Figure 2). The baseline characteristics for patients in each sub-group are set out in Table 2.


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  		Table 2 Baseline characteristics of each patient group

 
  1. DYS: intra-ventricular dyssynchrony as identified by a SF seen in both the SAX and transverse 4-CH views (n = 87, 54%). Radial velocity traces show a high premature (isovolumic contraction) septal velocity peak and non-mirrored septal/infero-lateral radial velocity profiles (Figures 2 and 3).
  2. FILLINGshort: no LVDYS, but inadequate filling due to a foreshortened AV delay (n = 21, 13%).
  3. FILLINGlong: no LVDYS but impaired filling due to a prolonged AV delay (n = 16, 10%).
  4. L–R interaction: no LVDYS, but exaggerated passive motion of a dysfunctional septum due to direct left–right interaction in the presence of an IVD >40 ms (n = 15, 9%).
  5. OTH: all others, with none the above findings (n = 22, 14%).
Forty patients (25%) displayed a combination of the above mechanisms; 36 of the DYS group and four patients with L–R interaction also had abnormal LV filling.

Response to cardiac resynchronization therapy
The baseline and follow-up parameters for each patient group are displayed in online supplements Tables 1 and 2. All patients with significant echocardiographic reverse remodelling were also clinical responders. However, the lack of reverse remodelling did not correlate with the lack of response. Among responders, 18 patients (15%) were pure clinical responders. Among responders with remodelling, 43 (35%) showed extreme remodelling ({Delta}LVESV > 25%), 25 (21%) marked remodelling ({Delta}LVESV: 15–25%), 24 (20%) modest remodelling ({Delta}LVESV: 10–15%), and 11 (9%) mild remodelling (<10% {Delta}LVESV). All responders (pure clinical responders and those with remodelling) belonged to one of the four proposed mechanistic sub-groups, whereas patients with no potentially amenable mechanism did not respond either clinically or with reverse remodelling.

Although the timing of follow-up showed large deviations among patients [median 6 months (3–6)], the average follow-up was similar in each subgroups and there was no correlation seen between time to follow-up and clinical response (P = 0.92) or degree of reverse remodelling (P = 0.94).

Identification of the subgroups
Subgroup 1, DYS
Of 87 patients, 77 (88%) showed resolution of the SF following CRT and all 77 responded clinically and with reverse remodelling. In all responders, CRT decreased the early septal velocity and delayed its maximum by >50% compared with baseline, resulting in a normalizing of septal motion. Ten patients retained the SF after CRT, and all failed to respond. Among these 10 patients with retained LVDYS, one patient had a proven LV lead displacement, and five had their LV lead placed in scarred myocardium (one in middle cardiac vein at an infarcted apex, four over posterolateral scar), whereas the remaining four patients had an anterior or lateral vein position in viable tissue. In responders, LV lead was predominantly lateral; however, 19% responded even with a sub-optimal lead position over an area of viable myocardium (15% anterior, 4% middle cardiac vein). In DYS, the degree of LV reverse remodelling was more pronounced (mean {Delta}LVESV: 29% in all responders) compared with other groups. Seven patients with previous partially infarcted septum and limited region of SF displayed modest remodelling (5–10% LVESV reduction). An SF was not seen in patients with full transmural septal infarct. Thirty-six DYS patients had additional inadequate filling patterns [pre-systolic MR (24 of 36) and fused E–A waves (36 of 36)].

Subgroup 2, FILLINGshort
This filling abnormality resolved in 19 of 21 after CRT and 18 of 21 improved clinically and 16 of 21 remodelled (mean {Delta}LVESV 20%). One patient did not improve and retained restrictive filling (this patient was intolerant of beta-blockers).The AV delay remained unchanged in two patients.

Subgroup 3, FILLINGlong
The AV filling pattern could be normalized in only 11 patients. These responded clinically and five remodelled (mean {Delta}LVESV 11%). FILLINGlong non-responders either retained a restrictive filling pattern after CRT (n = 3, extensive infarcted myocardium) or E–A fusion and residual pre-systolic MR persisted secondary to a resting sinus tachycardia preventing an adequate correction of the AV delay (n = 2, both intolerant of beta-blockers). Overall, the responders of FILLINGshort and FILLINGlong had less reverse remodelling compared with the DYS group.

Subgroup 4, left–right ventricular interaction
Fifteen patients with an infarcted inter-ventricular septum and a long IVD, with a clear direct L–R interaction, showed no remodelling although they all responded clinically (NYHA reduction ≥1). Despite the lack of reverse remodelling EF improved on average by 27% following an increase in LV end-diastolic volume. Additionally, the pulmonary artery pressure (PAP), which was highest in this subgroup at baseline (58 ± 14 mmHg), decreased significantly (45 ± 13 mmHg; P = 0.003) resulting in marked symptomatic improvement. Interestingly, in our cohort of London patients with serial BNP testing, L–R interaction patients had the highest pre-CRT BNP and demonstrated a significant, progressive fall in BNP after CRT (P = 0.003, n = 9 patients). Although 72 patients in total showed significant IVD (>40 ms), only 15 displayed left-right interaction.

Subgroup 5, OTH
The remaining 22 patients (14%) did not display any of the above mechanisms amenable to correction by CRT and were non-responders. Among them, 82% had lateral lead position and 18% suboptimal lead position.

Comparison of methods to predict response
We compared our mechanism-based approach with previously described DYS indices: Ts-SD1221 and DI4;1 QRS duration,3 the IVD,3 and the presence of abnormal filling. Long-axis DYS (Ts-SD12 and DI4) was technically difficult to measure in 46 pre-CRT patients (28%).

When used in isolation, all the DYS methods failed to predict response in an important number of responders (Ts-SD12: 45% of clinical and 37% of volume responders; DI4: 49% of clinical and 45% of volume responders; QRS duration ≥ 150 ms: 55% of clinical and 51% of volume responders; SF: 36% of clinical and 20% of volume responders; IVD: 44% of clinical and 47% of volume responders; abnormal filling: 52% of clinical and 47% of volume responders) (Table 3). However, when all amenable mechanisms were sought (using SF for LVDYS), responders were identified with 100% sensitivity and 55% specificity. Analysing Ts-SD12 in the different subgroups showed that in the DYS group, 37% of responders were not identified. In FILLINGshort, 38% of the responders were not identified, whereas in FILLINGlong, 19% of responders were missed. In the L–R interaction group, 54% would have been missed. Using DI4, 48% of responders in the DYS group would not have been identified, in FILLINGshort, 33% of responders would not have been identified, in FILLINGlong 25% of responders would have not been predicted, and in the L–R interaction group, 40% of responders had a low index of DYS. Table 4 shows the predictive value within each of the subgroups.


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  		Table 3 Prediction of response based on baseline dyssynchrony as a single parameter

 

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  		Table 4 Prediction of response by sub-dividing the population according to the underlying mechanism

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Funding
 References
 
In this study, we hypothesize that a response to CRT is linked to correcting one of at least four independent mechanisms, only one of which is intra-ventricular DYS (Figure 4). In this series, when a CRT device was appropriately implanted and optimized, the patient’s response could be predicted from the flowchart set out in Figure 4. From the analysis of the baseline echocardiographic data, we identified the following subgroups amenable to CRT.


Figure 4
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  		Figure 4 Proposed flowchart for the echocardiographic determination of responders to cardiac resynchronization therapy.

 
  1. Intra-ventricular DYS as identified by a SF.
  2. Foreshortened AV filling resulting in A-wave truncation/ablation.
  3. Prolonged AV delay, resulting in (partial) fusion of early and late filling ± pre-systolic MR
  4. Direct L–R mechanical interaction with important IVD in the presence of a partially or entirely infarcted septum.
Response was reliant on the correction of the underlying abnormality. Patients with SF remodelled significantly when the abnormal SF was corrected by CRT. Patients with a blunted A-wave due to short AV delays, in whom the A-wave was restored, responded in a predictable manner. It is difficult to explain how CRT corrects a previously truncated A-wave and this needs further investigation. In patients with long AV delays, response will depend on the ability to normalize filling which in turn is related to the severity of the underlying diastolic dysfunction. Patients with exaggerated left–right interaction in the presence of septal dysfunction (although none remodelled in this series) can improve their haemodynamics and symptoms mainly by correcting the IVD. Although other mechanisms, independent of the pre-CRT echocardiographic assessment, are involved in response to CRT, in this small cohort, patients not displaying any of the above mechanisms failed to respond either clinically or with remodelling.

Even if pacing viable myocardium appeared important, LV lead position did not vary significantly between responders and non-responders. Similarly, the aetiology of the cardiomyopathy and baseline MR did not preclude short-term response.

In order to identify LVDYS in a simple, robust manner, we propose to search for a SF as the mechanical consequence of LBBB-induced activation in the failing ventricle (Figures 1 and 2). The rationale for this has been predicted by mathematical models and described in experimental models of RV pacing.18–20 In a normal LV, all segments are activated almost simultaneously and deform (longitudinal shortening and radial thickening) at the same time. This results in both septal and lateral annuli being dragged towards the stationary apex. However, in cardiac failure with LBBB, the septum is activated first, and while it is developing a contractile force and shortening, the contralateral wall is not, and thus exerts a pulling effect on the latent opposite wall. As the septum contracts against a reduced load, it will move/shorten faster than normal during the isovolumic period (Figures 1 and 2). The combination of unloaded contraction of the septum, stretching the LW, followed by LW contraction, stretching the septum, leads to ineffective pressure build-up (dp/dt) and ejection.22

Methods previously described to identify responders, such as the Ts-SD1221 and DI4, 1 have been applied to the entire population of patients undergoing CRT rather than differentiating the other mechanisms amenable to CRT. In our population, assessing for DYS alone failed to identify a large proportion of responders regardless of the applied method. A combined approach to search for CRT correctable mechanisms yielded sensitivity of 100% of detecting responders in our cohort. The limited specificity (55%) is explained by the inability to correct the detected mechanism in all patients (persistent DYS or abnormal filling). Even if a proportion of predicted responders failed to improve, the reasons behind non-response could be identified, allowing for potential correction (i.e. repositioning of LV lead) and further response. Our findings are in agreement with the preliminary data from the PROSPECT trial,23,24 in which the echocardiographic DYS parameters (Ts-SD12, septal-lateral delay, septal-posterior wall motion delay, IVD) tested for their predictive value for response to CRT, showed that in addition to a large measurement variability among core labs, no single pre-determined echocardiographic DYS criterion tested was able to improve the patient selection of CRT significantly.

Ten patients with a pre-CRT SF retained it after CRT and did not respond, despite a well-functioning device. Besides problems with lead displacement (one patient), an inadequate pacing site (i.e. over a scar, n = 5 patients) resulted in sub-optimal LV pacing. However, the location of the lead itself did not seem to be of major influence, since 13% of DYS responders and 19% of all responders displayed sub-optimal anterior or middle cardiac vein position of their LV lead suggesting that pacing over an area of viable myocardium might be more important than the actual pacing site and that further investigation of the electrical activation pattern in these patients is warranted. Additionally, improved optimization of the pacemaker settings might influence the persistence of the SF after implant and needs further investigation. Inability to correct FILLINGlong in some patients with a persistent sinus tachycardia emphasizes the contribution of beta-blockade to response to CRT.

Response to cardiac resynchronization therapy
Although clinical response was previously considered unreliable and related to a ‘placebo effect’ of CRT,25 recently a relationship between clinical response and degree of reverse remodelling was reported,13 suggesting a spectrum rather than an absolute response/non-response to CRT. Our findings would also support that improved symptoms may reflect a true response to therapy. All our volume responders were also clinical responders whereas clinical response did appear without LV remodelling particularly in patients with L–R interaction (n = 15 of the 18 pure clinical responders). Although LVESV was unchanged, LVEDV increased as the abnormal passive septal motion was abolished, resulting in increased filling and LVEF. Additionally, they did show echocardiographic signs of ‘remodelling’ of their mitral flow pattern, atrial sizes and PAP suggesting a real response not related to a placebo effect. Reliance on an echocardiographic cut-off (such as {Delta}LVESV > 10%) would have resulted in misclassification of these patients. Furthermore, in our cohort of London patients with serial BNP testing, the patients with pure clinical response had the highest pre-CRT BNP and demonstrated a significant, progressive fall in BNP after CRT (P = 0.003, n = 9 patients).

Limitations
We present a relatively small sample size therefore there may well be further less frequent mechanisms amenable to CRT that we have not described in this paper. Specifically, patients with fast atrial fibrillation (not included in this series as they do not comply with standard published indications for CRT) have an additional potential mechanism of response with regards to rate control when CRT is combined with AV node ablation. The duration of follow-up of only 6 months (3–6) is relatively short- and long-term outcome is unknown.

Some patients (n = 40, 25%) showed a combination of mechanisms amenable to CRT suggesting that these patients might potentially have a greater response to CRT but this cumulative effect also requires further analysis.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Funding
 References
 
There exist multiple independent mechanisms governing response to CRT. In order to assess potential for response in an individual patient, each of these mechanisms should be examined. Patients should not be denied CRT on the basis of LVDYS indices alone.

Conflict of interest: none declared.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
References
 
C.P. was supported by a research grant from Medtronic.


   Footnotes
 
This paper was guest edited by Professor Martin J. Schalij, Leiden University Medical Center, Department of Cardiology, Albinusdreef 2, C5-P, 2300 RC, Leiden, The Netherlands.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 References
 

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