The CARE-HF trial enrolled patients with New York Heart Association (NYHA) class III or IV despite pharmacological treatment, with a QRS duration ≥120 ms, LV ejection fraction (EF) ≤35%, LV end diastolic diameter ≥30 mm/m² (height in m) and in sinus rhythm. Patients with a QRS duration between 120 ms and 149 ms required at least two of the following dyssynchrony criteria: (1) aortic pre-ejection delay >140 ms; (2) interventricular mechanical delay >40 ms; and (3) delayed activation of the posterolateral wall of the left ventricle as shown by any overlap between time from QRS to peak systolic movement of the posterior wall at m-mode and time from QRS to the beginning of the E-wave at pulsed Doppler transmitral flow. Patients with a QRS duration >150 ms did not require echo confirmation of dyssynchrony.

Of the 813 patients enrolled in the trial, 735 had an analysable echocardiographic examination. 13 including 92 patients with a QRS duration of between 120 ms and 149 ms. One-hundred patients aged 67.1 ± 10,4 years and randomized to the CARE-HF trial in five TDI interested and geographically close participating centers in Denmark, Germany and Sweden were eligible to the current sub study. The study was approved by the local ethics committees and all patients gave written informed consent.

Patients were examined in the left lateral position and tissue Doppler echocardiography was acquired in the apical 4 -chamber, 2-chamber and long-axis views using a VIVID-5 system with a 2,5 MHz transducer (GE-Vingmed Ultrasound, Horten, Norway). An average of 2–4 RR-intervals were stored as a cine loop (from p-wave to p-wave) on an optical disc for later off-line analysis (Echo-Pac Software, GE-Vingmed Ultrasound, Horten, Norway). Systole was defined as the ejection time from opening until closure of the aortic valves as measured by tissue velocity imaging (TVI) in the apical long-axis view 14. The time from onset of the QRS-complex until opening of the aortic and pulmonary valves were defined as the pre-ejection periods. From the TVI loops colour Doppler TVI analysis was performed in each of the apical views. The 16 segment LV-model of the American Society of Echocardiography was used for regional analysis of the extent of dyssynchrony 15. The extent of dyssynchrony during systole was evaluated regionally by tissue synchronisation imaging (TSI) (Figure 1). The TSI-start was set to the aortic valve opening and the TSI-end to the aortic valve closure and the TSI cut-off value was preset to 85 ms. This cut-off value, assumed to indicate important intra-ventricular dyssynchrony, was chosen based on the application of the method in previous patients in our echo-laboratory, and now tested in a prospective trial.

Presence or absence of delayed longitudinal contraction (DLC), i.e. motion towards the apex following closure of the aortic valve was recorded by strain rate (SR) technique in each of the 16 LV segments 16. Motion toward the apex after closure of the aortic valve was only registered as DLC if negative SR documented that the motion reflected true shortening (Figure 1). All the TVI analyses were performed twice by the same investigator and the mean of the two measurements was used. Intra- and inter-variability was fairly low. The coefficient of variation for TSI and DLC analysis was 3 and 5%, and 4,5 and 9%, respectively.

Atrio-ventricular dyssynchrony (LVFT/RR) was considered present if the left ventricular filling time (LVFT) measured from the mitral valve Doppler in-flow signal was <40% of the cardiac interval (R-R). The inter-ventricular mechanical delay (IVMD), was defined as the time difference between the onset of forward flow in the LV outflow tract and RV outflow tract and >40 ms was considered indicative IVMD 17

Other aspects of the study methods such as assays for NT-proBNP have been published in detail 17.

Eight hundred and thirteen patients were recruited to the CARE-HF trial of which 100 participated in the tissue Doppler sub study. Only nine patients in the sub study had QRS below 150 ms. The characteristics of the patients in the sub study were similar to those in the main-study, except for evidence for more intense pharmacological management (Table 1 and Table 2). Echocardiographic measures of dimensions and LV EF were however similar and there was only a trend to higher (N.S.) NT-proBNP.

Thirty-four patients (34%) had a LVFT/RR <40%, 60 (60%) had inter-ventricular dyssynchrony and the median IVMD was 47.9 ms (Table 3).

Eighty-six patients (86%) had intra-ventricular dyssynchrony on TSI. The distribution of TSI-measured dyssynchrony is shown in figure 2. The median number of affected segments was four and all showed dyssynchrony in one or more basal segment. Mid-segments were affected in 69 patients, with a median of two affected segments, but none had apical dyssynchrony. Eighty-five patients (85%) had intra-ventricular dyssynchrony measured by the SR technique, all 85 patients having affected basal segments, with a median two out of six segments, 70 having mid-segments affected but none having apical dyssynchrony (Table 3).

On univariate analysis, patients with dyssynchrony measured by TSI were more likely to be women p = 0.001, have IDCM p = 0.002 and have greater QRS duration p = 0.03. Findings were similar for intra-ventricular dyssynchrony by DLC (Table 4).

On multi-variate analysis woman, patients with IDCM and measures of ventricular dilatation and dysfunction, but not QRS duration, predicted the presence of dyssynchrony by TSI and DLC.

Most patients had intra-ventricular dyssynchrony using both methods but measurements of TSI are substantially faster. Accordingly, we investigated the agreement between the methods analysing every segment separately in the 16-segment model 15 to determine wheather their results were interchangeable. Within the six basal segments, three had a perfect match and the Kappa coefficient was 0.86–1.0. The agreement within the mid-segments was even better with three segments showing perfect match and the Kappa coefficient being 0.92–1.0. These findings suggests that TSI and DLC are interchangeable methods with which to assess dyssynchrony.

LVFT/RR <40% was present in 33% and IVMD in 51% of patients with intra-ventricular dyssynchrony (TSI or DLC). Conversely, 85% of the patients with IVMD >40 ms had intra-ventricular dyssynchrony.

All three types of dyssynchrony co-existed in only 23% of the patients (Table 5).

Patients with cardiomyopathy had shorter LVFT and more LVFT/RR than those with ischemic heart disease, 45,3% vs. 21,3%, p = 0.02. IVMD was present in 69% of patients with IDCM and 48,9% of those with IHD, p = 0.09. Similar numbers of patients with IDCM and IHD had intra-ventricular dyssynchrony, with the basal lateral and posterior segments most commonly affected (Figure 3), but patients with IDCM had more affected segments, with a median of 4(3, 5) vs. 3(1, 4), p = 0.027 (Table 3 and 5).

Many studies show that QRS duration predicts mortality in patients with heart failure. It is assumed by many that this reflects more severe dyssynchrony. However, QRS also reflects LVEF 21. There are few data that show whether dyssynchrony by imaging is prognostically important. In the CARE-HF study, IVMD was associated with a better prognosis in the control group. One small observational study 8 with an unusually high mortality found that intra -ventricular dyssynchrony but not IVMD or QRS predicted mortality.

The QRS width has been shown to be related to both inter- and intra-ventricular dyssynchrony but during long-term follow up of patients with dilated cardiomyopathy only intra-ventricular dyssynchrony was related to cardiac events 78. Another important issue is the capability to predict LV reverse remodelling after CRT and even if IVMD has been shown to predict response to CRT 22 most investigators consider intra-ventricular dyssynchrony to select responders to CRT 2324. On the other hand, IVMD is easy to measure and in this study 85% of the patients with IVMD >40 ms also had intra-ventricular dyssynchrony which could make it reasonable to include IVMD in clinical routine.

In this study, we found a high prevalence of intra-ventricular dyssynchrony with a high agreement between the two methods suggesting that they are inter-changeable in terms of evaluating intra-ventricular dyssynchrony. Thus a postsystolic DLC is associated with a delayed maximal velocity in the same region during systole.

Since the TSI analyse is substantially faster to perform, TSI may be used in clinical routine. In a previous report by Gorscan et al a cut-off value of >65 ms had a sensitivity and specificity of 87% and 100%, respectively, to predict the initial response to CRT 25. LV reverse remodelling after three months of CRT may also be predicted by TSI with a sensitivity of 87% and specificity of 81% 26. Van de Veire et al found there was an excellent correlation between LV dyssynchrony measured manually by color-coded TDI and automatically using TSI 27. The recently published PROSPECT trial, an observational study, tested twelve different techniques to describe dyssynchrony and many of those turned out to be difficult, due to high variability, to use in a multicenter study 28. As a mater of fact, those techniques which could be said are easiest to use i.e. lateral- septum maximal velocity difference (T_S -lateral- septum), LVFT/RR, APE and IVMD turned out to be the most useful. This further support the use of the fast and simple TSI technique (Fig 4, 5). In our preliminary analysis of outcome data at least two TSI positive segments are needed to predict a responder to CRT.

However, analysis of CARE-HF suggests that the initial response of LV function to CRT is a poor predictor of the effect of intervention on long-term mortality. Strain rate analyses of delayed longitudinal contraction (DLC) often require an off-line approach and are therefore more time-consuming. The main advantage with strain rate is its ability to differentiate between active systolic contraction and passive motion. The number of segments with DLC is related to the improvement in LV systolic function by biventricular pacing during long-term follow-up 11. Thus, both methods might be useful to select patients who get greater benefit from CRT. However, randomized controlled trials (RCTs) that might be difficult to design will be required to test this hypothesis.

We found patients with cardiomyopathy to have shorter LVFT than those with ischemic ethiology and more patients had LVFT/RR <40% of the R-R interval. There was a tendency to more patients having intra-ventricular dyssynchrony in the CMP group compared to IHD, and there was a difference in the number of affected segments 4(3, 5) vs. 3(1, 4), p = 0.027. Thus, two types of dyssynchrony and combinations of dyssynchrony were more common in patients with dilated cardiomyopathy. Similar findings with signs of less dyssynchrony in patients with ischemic heart failure were shown in a study by Zwanenburg et al using Magnetic resonance imaging 29. Thus, CRT might be less effective in ischemic patients compared with patients with cardiomyopathy (but CARE-HF shows ischemic patients to have smaller effect on LV function but similar effect on long-term mortality). This has been observed in i.e. the MIRACLE trial in which both non-ischemic and ischemic patients improved regarding reverse remodelling and enhanced EF but the changes was statistically significantly smaller in the ischemic group 30. This difference has also been observed in other studies 3132 and could thus be explained by less dyssynchrony in the ischemic patients but perhaps also by the ischemic patients having more scar tissue.

The PROSPECT (Predictors of response to cardiac resynchronization therapy) study was recently reported at the hotline session during the ESC meeting 2007 and commented on by E. S Zegers and F.W.A Verheugt in the Euro Heart J 33. This is a multicentre study including 426 patients with standard indication for CRT. The aim was to identify echocardiographic and tissue Doppler measures of dyssynchrony and their ability to predict response to CRT. It was found that presence of signs of dyssynchrony was linked to 11–13% additional clinical response to CRT and 13–23% additional response for reverse remodelling compared to absence of measures of dyssynchrony. One limitation of our study is we do not report on outcome of the patients, however, that was not the aim of this study but obviously it is important to identify signs of dyssynchrony. Another finding in the PROSPECT study was a high inter-variability measuring signs of dyssynchrony and therefore a need for simplification of methodology. However, it is important to remember this was not a RCT but an observational study which means that the importance of dyssynchrony can not be fully estimated. TSI might be such a simple method as described in this paper. It is also easy to measure LVFT/RR and IVMD and using these three signs of dyssynchrony in clinical routine might be sufficient to identify potential responders to CRT.