This study demonstrated the relationship between several echocardiographic dyssynchrony markers and the important outcome variable of long term survival following CRT. A large series of consecutive patients were included using a prospective longitudinal study design with pre-specified end-points. The echocardiographic approach revealed a relatively high yield (89%) in consecutive patients referred for CRT. Baseline clinical variables were balanced overall in those patients with and without dyssynchrony, however the lack of dyssynchrony was significantly more prevalent in those with ischemic disease. Radial dyssynchrony and IVMD were also related to baseline QRS width. As expected from this severely ill group of heart failure patients, there were a large number of the unfavorable events of death, heart transplant or LVAD. Using pre-defined cut-offs, baseline dyssynchrony before CRT by the Yu Index, speckle tracking radial strain anterioseptal to posterior wall delay, and IVMD were all associated with more favorable survival free from transplant or LVAD. The TDI OWD with the pre-defined cut-off of ≥ 65 ms had a trend for association with event-free survival (p=0.075), however, an OWD cut-off of ≥ 80 ms by post hoc
analysis became significantly associated (p=0.011). Of note, the Kaplan-Meier curves for each of these TDI indices did not diverge until after the first 6 months after CRT, which was the follow-up interval of PROSPECT. Of the 191 patients with both Yu index and radial dyssynchrony data available, 128 (67%) were concordant for dyssynchrony using pre-specified cut-off values. When considering 8 additional patients with borderline dyssynchrony values ± 5 ms for Yu index and ± 10 ms for radial dyssynchrony, concordance increased to 71%. The exact reason for discordance is unknown. Perhaps TDI longitudinal velocity and speckle tracking radial strain assess different aspects of dyssynchrony and provide additional information. 15
When adjusted for covariates of ischemic etiology and QRS width, the Yu Index and radial strain remained independently predictive of outcome. Subgroup analysis demonstrated that patients with narrower QRS width 120–150 ms who lacked radial dyssynchrony had a particularly poor survival. These observations strongly support the association of echocardiographic dyssynchrony with long-term patient outcome after CRT.
Several previous studies have also shown the ability of echocardiographic mechanical dyssynchrony to predict response to CRT.4,5,7,8,15–17,20–25
Baseline dyssynchrony has been related to improvement in heart failure class, 6-minute walk distance, quality of life score, EF and reductions in end-systolic volumes. However, the multicenter PROSPECT study of predictors of response to cardiac resynchronization therapy failed to show conclusively that a single echocardiographic dyssynchrony measure was highly predictive. 9
Although there have been over a hundred published articles supporting the utility of echocardiographic dyssynchrony to predict CRT response, PROSPECT has had a particularly high impact on clinical opinion because of its prospective multicenter design. CRT guidelines continue to use QRS width as a surrogate for mechanical dyssynchrony. 26
Several acknowledged limitations of PROSPECT included a low yield of feasibility, high variability using three different echocardiographic systems and software, and three different echo core labs. 11,12
For example, the overall yield for routine measures in PROSPECT such as end-systolic volumes was approximately 67%, indicating poor image quality in a third of patients. Furthermore, TDI Yu Index was feasible in only 50% of attempted studies, in contrast to the present study with a yield of 89% of consecutive CRT patients. Importantly, the follow-up was limited to 6 months in PROSPECT which may likely have been too short a duration to demonstrate the relationship of dyssynchrony with patient outcome.
Specific echocardiographic measures of dyssynchrony predictive of outcome following CRT have been reported by several authors. Bax et al. demonstrated that a TDI OWD of ≥ 65 ms was associated with a lower incidence of heart failure hospitalizations and death in the first year following CRT. 5
This OWD cut off of 65 ms in our present study had a strong trend to significantly predicting survival free from transplant or LVAD, however, we did not include heart failure hospitalizations as and end-point. Pitzalis et al. used M-mode to show that an anteroseptal to posterior wall delay of ≥ 130 ms successfully predicted outcome. 23
We and others have had more success with speckle tracking radial strain to assess anteroseptal to posterior wall delay, with a favorable predictive value using the same 130 ms cut-off value. 7
Bank et al. showed that radial strain by speckle tracking was also predictive of response to CRT in a multicenter study. 27
Analyses from the CARE HF trial used a cut-off of 49 ms for IVMD to demonstrate its value to predict outcome following CRT. 28
We selected a pre-defined IVMD cut-off of ≥ 40 ms as originally described and also used in the PROSPECT trial. 9,18
More recently, Chailil et al. used cardiac magnetic resonance imaging to assess dyssynchrony and predict mortality following CRT. 29
Others have shown that mechanical dyssynchrony either independently or when combined with clinical markers is associated with a more favorable survival following CRT. 30
Furthermore, echocardiographic dyssynchrony has been shown to be a marker for mortality in heart failure patients with narrow QRS duration using TDI or after myocardial infarction using velocity vector imaging. 31
We observed that the absence of radial dyssynchrony in patients with QRS 120–150 ms to be associated with a particularly high probability of death, transplant or LVAD. Radial dyssynchrony was not associated with outcome in patients with QRS > 150 ms. However, we observed that the Yu Index was particularly associated with outcome in patients with QRS >150 ms. The exact reason for these results is unclear, but suggests that the TDI Yu index and speckle tracking radial strain may be assessing different aspects of LV dyssynchrony. 15
More recently, radial and transverse strain by speckle tracking was shown to be associated with ejection fraction response and survival after CRT in a separate multicenter study using different echocardiographic equipment and software.31
In summary, this present study demonstrates that baseline echocardiographic dyssynchrony is associated with a more favorable outcome following CRT, and that patients who lack dyssynchrony may be identified as being at comparatively higher risk for death, transplant or LVAD following CRT.
The present study was not part of a randomized trial, and the relationship of echocardiographic dyssynchrony to survival in those who do not undergo CRT remains unknown. Although the absence of echocardiographic dyssynchrony appears to be a marker for a worse prognosis in patients following CRT, the potential influence of CRT on outcome in patients without dyssynchrony remains unknown. However, it is presently difficult to withhold CRT from patients who meet current CRT implantation criteria to elucidate this point. Another limitation was that echocardiographic dyssynchrony analysis could not be successfully performed on all consecutive CRT patients, and 10–11% of patients did not have adequate image quality for quantification. Furthermore, high quality images appear to especially important for speckle tracking analysis. 7,15,32
It is acknowledged that these echocardiographic methods are operator dependent, and require user experience. In particular, technical difficulties with speckle tracking strain occurred in regions of myocardial scar, and appeared to be more robust in patients with nonischemic cardiomyopathies. However, reproducible results may be achieved with a systematic core-lab approach, detailed in the methods. A limitation of the study design may be considered that all survival free from heart transplantation or LVAD was used as the primary end-point, rather than all cause mortality. However, heart transplantation and LVAD implantation in our institution are utilized only in heart failure patients with a very limited life span anticipated without these interventions. Another limitation was that markers of CRT response used in other clinical trials, such as heart failure hospitalizations, 6-minute walk distance, peak myocardial oxygen consumption, LV reverse remodeling or EF improvement were not part of the present study. It may be considered a limitation that ischemic etiology may influence response to CRT from scar burden or lead positioning and have confounding effects. 33,34
Analysis of scar burden and lead positioning was not part of the current study. We demonstrated that when adjusting specifically for ischemic etiology, the Yu index and speckle tracking radial strain remained independently associated with survival. Our subgroup analysis on heart failure etiology and QRS width provided additive information which may be of clinical impact. Recent data support the potential utility of echocardiographic dyssynchrony in patients with less wide QRS duration as an adjunct to clinical decision making. 22
It remains uncertain how these data will directly influence clinical practice, and ongoing further study is warranted.
This study demonstrated the association of echocardiographic dyssynchrony with long term survival following cardiac resynchronization therapy (CRT). We studied 229 consecutive patients with routine CRT indications (symptomatic heart failure, reduced ejection fraction and widened QRS ≥ 120 ms) of which 210 (89%) had baseline echocardiographic dyssynchrony data available. Dyssynchrony was pre-specified as tissue Doppler longitudinal velocity opposing wall delay ≥ 65 ms, 12-site standard deviation (Yu Index) ≥ 32 ms, speckle tracking radial strain anteroseptal to posterior wall delay ≥130 ms, or pulsed Doppler interventricular mechanical delay ≥ 40 ms. Of 210 patients, there were 62 unfavorable events over 4 years after CRT: 47 deaths, 9 transplants, and 6 left ventricular assist device implantations. All echo dyssynchrony indices were significantly associated with a more favorable long term prognosis than patients without dyssynchrony, except tissue Doppler velocity opposing wall delay became significant at ≥ 80 ms. When adjusted for covariates of ischemic etiology and QRS width, the Yu Index and speckle tracking radial strain remained independently predictive of outcome. Subgroup analysis demonstrated that patients with narrower QRS width 120–150 ms who lacked radial dyssynchrony had a particularly poor survival. Although this study has identified the absence of echocardiographic dyssynchrony as a marker for a less favorable prognosis in patients who undergo CRT for routine indications, the potential influence of CRT on outcome in patients without dyssynchrony remains unknown. These observations strongly support the association of echocardiographic dyssynchrony with long-term patient outcome after CRT.