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How to discriminate responders from non-responders to cardiac resynchronisation therapy

Christoph Stellbrink*, Ole-Alexander Breithardt, Anil-Martin Sinha and Peter Hanrath

Medizinische Klinik I, Klinikum der RWTH Aachen, Pauwelsstrasse, Aachen, Germany

Received 3 May 2004; accepted 24 May 2004.

* Christoph Stellbrink, Medizinische Klinik I, Klinikum der RWTH Aachen, Pauwelsstrasse 30, 52057 Aachen, Germany. Tel.: +49-241-8089945; fax: +49-241-8082414
cstellbrink{at}ukaachen.de

Abstract

Cardiac resynchronisation therapy (CRT) has been increasingly accepted as an adjunct therapy to drug treatment for heart failure patients with ventricular conduction delay. Nevertheless, using implant criteria from current guidelines, 20–30% of patients show no or only minor functional benefit. One important reason for this is the fact that these criteria rely mainly on QRS width as a measure of left ventricular dyssynchrony. However, QRS width may not always correlate well to mechanical dyssynchrony which is the main abnormality to be treated by CRT. Several methods have been proposed to assess left ventricular dyssynchrony, such as cardiac magnetic resonance imaging (MRI) or echocardiography. Because MRI is not repeatedly available in pacemaker patients, echocardiography is emerging as the most promising technique both for the identification of therapy responders and the assessment of optimal CRT delivery. However, none of the proposed echocardiographic criteria has yet been validated in prospective trials. This review summarizes the current knowledge on the optimal identification of therapy responders to CRT.

Key Words: Cardiac resynchronisation therapy • Pacemaker • Heart failure • Left bundle branch block

Introduction

Several studies have demonstrated the benefit of cardiac resynchronisation therapy (CRT) with regard to acute hemodynamic improvement,1–4 improved exercise capacity,5–7 reverse remodeling8–10 and combined mortality and hospitalizations.11 However, using currently accepted implant criteria12 about 20–30% of patients may not show substantial functional benefit from CRT.7 As CRT aims to correct the negative hemodynamic impact of ventricular dyssynchrony, it is generally accepted that the degree of baseline ventricular dyssynchrony predicts the response to CRT. However, currently defined implant criteria rely primarily on electrical rather than mechanical criteria of ventricular dyssynchrony, i.e., QRS width.12 Therefore, other criteria for predicting cardiac mechanical dyssynchrony are currently being sought for. This article summarizes the current status for identifying CRT responders.

Implantation criteria derived from completed trials

The first data demonstrating a positive hemodynamic effect of CRT were acute studies showing an increase in the slope of left ventricular pressure rise (LV+dP/dt),3 cardiac output1 or an improvement of LV pressure–volume loops.2 It could also be demonstrated that patients with low baseline +dP/dt and a QRS width above 155 ms were almost exclusively acute hemodynamic responders to CRT.13 The data obtained in these hemodynamic studies and some early feasibility studies were used to identify possible responders to CRT in the early prospective cross-over trials evaluating the functional benefit associated with CRT over 3–6 months. However, these trials included only a limited number of patients. Table 1 summarizes the implant criteria used in some of the most important prospective CRT trials. Whereas the QRS width cut-off used in the MUSTIC trial5 (sinus rhythm limb) was 150 ms, the PATH-CHF trial,6 also showing significant benefit, included patients with a QRS of only 120 ms or above. Thus, in the larger prospective trials with parallel design more liberal inclusion criteria were used, 120 ms in the Contak CD study14 and 130 ms in the MIRACLE study.7 All studies included patients with heart failure functional class III–IV. Some of the later studies, e.g., the Contak CD trial and the PATH-CHF II study, also included patients in functional class II although the benefit in this patient group has not been unequivocally demonstrated. The data from these larger trials, especially the MIRACLE trial, have been adopted in the actualized ACC/AHA/NASPE guidelines for the implantation of cardiac pacemakers.12 It is estimated that about 10% of all heart failure patients may potentially benefit from CRT using these criteria.15


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  		Table 1 Implant criteria in different CRT trials

 
Some other criteria have been identified in small studies including the presence of functional mitral regurgitation before implantation,16 an LV+dP/dt of less than 700 mmHg/s,13 a left ventricular enddiastolic diameter of more than 55 mm, an ejection fraction of equal or less than 35% and a low maximal oxygen consumption during cardiopulmonary exercise testing.17

The major limitation of all trials was that they used only the QRS width, i.e., an electrical parameter, as a parameter to assess left ventricular dyssynchrony although it is the mechanical dyssynchrony which is the main correctable cause of reduced pump function in these patients. The correlation between electrical and mechanical dyssynchrony is weak. This is underscored by data showing that despite the dependence of the acute hemodynamic improvement to CRT on baseline QRS width shortening of the QRS complex is not correlated to the hemodynamic effect, especially in LV pacing.13 In addition, baseline QRS width in the MIRACLE trial did not appear to correlate well to clinical improvement.7 Therefore, it must be assumed that it is not only the width of the QRS complex alone but also the type of conduction delay that influences the mechanical dyssynchrony which is the true cause of inefficient systolic left ventricular contraction in these hearts.

Methods for assessing left ventricular dyssynchrony

There are principally two methods that have been used in clinical studies for assessing left ventricular dyssynchrony: magnetic resonance imaging (MRI) and echocardiography. Early experimental data suggest that cardiac MRI may be a suitable tool for quantifying systolic contractile dyssynchrony.13 However, whereas cardiac MRI may be regarded as the gold standard for assessing left ventricular wall motion, it is expensive, not generally available and cannot be repeatedly performed in patients with an implanted device. Thus, the assessment of left ventricular mechanical dyssynchrony and its correction by CRT has emerged as an intense area of research for echocardiography. Table 2 summarizes the echocardiographic methods that have been described in the literature for characterization and quantification of left ventricular mechanical dyssynchrony. According to the imaging modality used, the parameters used in the assessment of left ventricular dyssynchrony may be classified into parameters derived from M-mode, conventional Doppler, two-dimensional echocardiography and tissue Doppler imaging (TDI).


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  		Table 2 Echocardiographic parameters for assessment of left ventricular dyssynchrony

 
M-mode echocardiography
The only parameter from M-mode echocardiography that has been studied in correlation to clinical response to CRT is the septal-to-posterior wall motion delay. Pitzalis et al.18 demonstrated that reduction of the systolic wall motion delay between the interventricular septum and the posterior wall correlates with changes in ejection fraction and left ventricular diameters. Interestingly, in the same study, there was no correlation of these parameters to the interventricular mechanical delay, as determined by conventional Doppler echocardiography.

Conventional Doppler echocardiography
Conventional Doppler echocardiographic criteria may be used to assess the interventricular asynchrony or the delay of left ventricular ejection. Interventricular asynchrony is calculated by measuring the time difference between the onset of the pulmonary and aortic Doppler flow signal. A time difference of >40 ms is considered abnormal.19 Alternatively, the left ventricular pre-ejection period can be measured from the onset of the QRS complex (or the pacing spike, respectively) to the onset of the aortic Doppler flow signal. It is usually less than 140 ms in duration (Fig. 1).20 This measurement correlates to the isovolumic contraction phase of left ventricular systole. Both measurements are affected by changes in afterload, e.g., pulmonary or systemic hypertension. Other measures of systolic function are the measurements of the aortic velocity time integral as an indicator of cardiac forward output or the calculated myocardial performance index.21 In addition, the pulsed-wave mitral valve inflow profile can be used to assess the influence of CRT on diastolic function. It may be useful to find the atrioventricular delay providing optimal left ventricular filling22 but this method has not been validated in heart failure patients undergoing CRT. Moreover, assessment of the continuous wave mitral regurgitant jet is helpful to assess the presence of pre-systolic mitral regurgitation (MR) and the degree of systolic functional MR.23 The slope of the MR jet can be used to estimate left ventricular +dP/dt.



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  		Fig. 1 Determination of the left ventricular pre-ejection period. The left ventricular pre-ejection period is delineated by the two dotted vertical lines. It is calculated as the time difference between the onset of the QRS complex in the surface ECG (left arrow) and the onset of the aortic flow signal in the pulsed-wave Doppler echocardiographic image (right arrow). In this example the pre-ejection period is prolonged with 166 ms.

 
Two-dimensional wall motion analysis
Breithardt et al.24 used a semi-automatic endocardial border detection system for analysis of different left ventricular wall motion patterns. They could demonstrate that patients with a high degree of left ventricular dyssynchrony using this technique were more likely to show acute improvement in left ventricular +dP/dt than those with no or only little left ventricular dyssynchrony. With the addition of echocardiographic contrast in the left ventricular cavity, Kawaguchi et al.25 could demonstrate that the reduction in left ventricular dyssynchrony by CRT correlated well with the increase in ejection fraction. Currently, real-time three-dimensional echocardiography is being evaluated as a potentially superior modality but no published data exist by the time of this writing.

Tissue Doppler echocardiography and strain rate imaging
Many researchers have focused on TDI in the evaluation of CRT as it allows relatively easy quantification of regional wall motion abnormalities and changes. In the meantime, TDI is available in the latest-generation ultrasound machines of most manufacturers. It is especially useful for the assessment of left intraventricular dyssynchrony. Several parameters have been proposed: Sogaard et al.26 quantified the extent of the basal left ventricle with delayed systolic longitudinal contraction which appeared to correlate with changes in ejection fraction during CRT. Yu et al.27 calculated the standard deviation of the time to peak systolic contraction of 12 left ventricular segments, a parameter that correlated both to changes in ejection fraction and left ventricular size during CRT. Strain rate imaging may be superior to TDI because it assesses myocardial deformation rather than motion. In patients with ventricular dyssynchrony, there may be dissociation between motion and deformation and thus, strain rate imaging may predict the effects of CRT more reliably than TDI.28

When summarizing the available evidence on the various echocardiographic methods used for analysis of left ventricular dyssynchrony and its correction by CRT, several major problems remain: (1) The fact that many parameters exist makes them difficult to be integrated into clinical routine. Clearly, a consensus is desirable which of these parameters are the most useful and should be routinely used in screening patients for CRT. (2) The endpoints used for defining responders are different in the published studies. Whereas some investigators correlated their results to hemodynamic effects of CRT, others have searched for correlations to measures of left ventricular remodeling. This may be important because earlier data suggest that the hemodynamic effects of CRT correlate only poorly to the reverse remodeling effects of CRT.8 (3) Most importantly, all echocardiographic studies thus far were post-hoc analyses published from single-center experience. Therefore, the different parameters proposed need to be validated in prospective randomized trials before general recommendations can be made for their implementation into daily clinical routine.

Conclusion

The response to CRT is largely determined by the baseline degree of inter- and intraventricular dyssynchrony. Current implant criteria for CRT devices are based on electrical parameters (i.e., QRS prolongation) rather than mechanical criteria. Therefore, up to 30% of patients do not seem to show significant improvement with CRT using currently accepted criteria. The definition of echocardiographic indices of ventricular dyssynchrony is under intense research at present and several indices have been proposed that may or may not prove useful in a prospective evaluation. It is high time for a prospective trial to evaluate these different parameters with regard to their impact on the efficacy of CRT. These data will hopefully provide a better basis for the clinical decision which patient is likely to benefit from this new therapy in heart failure. As long as these data are not available, physicians will have to rely on the simple clinical parameters as proposed in the currently available guidelines.

References

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