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Archives of cardiovascular diseases
Volume 102, n° 1
pages 65-74 (janvier 2009)
Doi : 10.1016/j.acvd.2008.06.019
Received : 12 April 2008 ;  accepted : 23 June 2008
Selection of patients responding to cardiac resynchronisation therapy: Implications for echocardiography
Sélection des patients répondeurs à la stimulation de resynchronisation cardiaque : quelles perspectives pour l’échocardiographie ?
 

Erwan Donal , Christian de Place, Christophe Leclercq, Jean-Claude Daubert
Service de cardiologie, CHU de Pontchaillou, rue Henri-le-Guillou, 35033 Rennes cedex 01, France 

Corresponding author. Fax: +33 (0)2 99 28 25 10.
Summary

Echocardiography is an essential facet of monitoring patients with heart failure. However, results of echocardiographic detection and quantification of mechanical dyssynchrony are not currently recommended as grounds for the deployment of biventricular (Biv) resynchronisation therapy. Ten years of research in the field of dyssynchrony within echocardiography have resulted in two negative studies which have, to some extent, discredited this technique. However, the research conducted has at least allowed us to refine our understanding of mechanical dyssynchrony and its management. New quantification techniques and generalised access to digital imagery and processing have renewed hopes that the performance of echocardiography in this field will soon improve. We therefore propose new criteria, to be evaluated as per PROSPECT standard methodology. In the review of the literature presented here, we suggest combining the echocardiography parameters for an individual and physiopathological approach, while waiting for more prospective studies to be conducted before issuing any recommendations.

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Résumé

L’échocardiographie est indispensable au suivi de l’insuffisant cardiaque. Toutefois, la recherche et la quantification d’un asynchronisme mécanique par l’échocardiographie ne sont pas actuellement recommandées pour poser l’indication d’une resynchronisation par stimulation biventriculaire (Biv). Dix années de recherche dans le domaine de l’asynchronisme en échocardiographie se soldent par deux études négatives qui ont porté un certain discrédit sur la technique. Toutes ces recherches ont néanmoins permis d’affiner notre compréhension de l’asynchronisme mécanique et des moyens de l’appréhender. De nouveaux outils de quantification et l’accès généralisé à l’image numérique, accessible à différents post-traitements, permettent d’espérer l’amélioration prochaine des performances de l’échocardiographie dans ce domaine. De nouveaux critères sont proposés, il faudra les évaluer selon le standard méthodologique de Prospect. Nous proposons, dans cette revue, une approche combinant les paramètres échocardiographiques pour une approche individuelle et physiopathologique, attendant de futures études prospectives avant de faire une quelconque recommandation.

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Keywords : Heart failure, Mechanical dyssynchrony, Echocardiography, Myocardial deformation, Doppler tissue

Mots clés : Insuffisance cardiaque, Asynchronisme mécanique, Échocardiographie, Déformation myocardique, Doppler tissulaire


Introduction

Thanks to a largely homogeneous body of data, biventricular (Biv) cardiac resynchronisation therapy now has its place amongst the treatment options available for systolic heart failure [1, 2]. Published in 2005, the CARE-HF study demonstrated that pacing (Biv) combined with optimal pharmacological treatment significantly reduced major cardiovascular-related morbidity and mortality irrespective of cause [3, 4]. Thus, the American and European recommendations published in 2005 and subsequently 2008 propose Biv pacing for patients whose heart failure remains symptomatic of NYHA class III–IV despite optimal pharmacological therapy, with a QRS width greater than or equal to 120ms, left ventricular end diastolic diameter greater than or equal to 55mm and an altered left ventricular ejection fraction (LVEF less than 35%) [1, 5]. Despite a high percentage not responding to treatment (≈30%), in 2007 QRS width was still the criteria of choice for determining dyssynchrony, on which the decision to perform cardiac resynchronisation was based [6, 7, 8].

Findings of multicentre studies

Before the PROSPECT [9] and RETHINQ studies [10], only CARE-HF had proposed echocardiographic criteria for the inclusion of patients, but these were only used in 11% of cases and therefore have no predictive value [9, 11, 12, 13, 14, 15, 16, 17, 18]. Nonetheless, many (particularly observational) studies in small populations are regularly published showing that patient selection could be improved by the use of such methods as echocardiography [11, 19, 20, 21]. Several approaches have been suggested but it is neither pertinent nor within the scope of this article to review them all.

Two approaches (spatial dyssynchrony parameters) have been explored in both single-centre studies and a multi-centre evaluation with a centralised review board: PROSPECT and RETHINQ [9, 13, 17, 22, 23]. The ability of M mode and tissue Doppler (velocities) to predict a functional result was found to be disappointing in the multi-centre study. Both these methods show poor reproducibility and feasibility. In addition, the echocardiography data in the PROSEPCT study was only slightly more specific and sensitive than that of QRS, when it came to the screening of potential patients “responding” to Biv resynchronisation therapy. It should be noted that the added value of a combination of these dyssynchrony quantification methods has not been explored against the value of any method assessed individually. Both these methods test for the presence of dyssynchrony on one side versus the other. This is known as testing for spatial dyssynchrony. Temporal dyssynchrony parameters also exist (Figure 1). They have been used in a multi-centre trial (DESIRE) [24]. Testing for a “systole–diastole” overlap appears feasible in most cases and is of major positive predictive value. Unfortunately, this criterion is most often found only in cases of severe electric dyssynchrony (very wide QRS).

Echocardiography modalities: their use and potential advantages

Echocardiography modalities can be used to gain a better understanding of left ventricular mechanical function. They should be used when the examination is normal or when contractility is not severely affected… before analysing ischemic heart disease or globally hypokinetic dilated cardiomyopathy (situations in which myocardial kinetic abnormalities are most difficult to quantify).

Each of these tools has its limitations and it will no doubt be necessary to take a holistic and multi-parametric approach before being able to conclude as to whether mechanical dyssynchronies predictive of a favourable response to resynchronisation therapy actually exist. Convergence amongst parameters is of greater value to us than a few parameters studied in isolation [25]. Left ventricle contractility is a complex process involving three layers of myocardial fibres, each of which has a relatively distinct function:

the endocardial layers are responsible for longitudinal contraction, i.e. from the base of the heart towards the apex of the left ventricle. These layers are more prone to myocardial ischemia;
the middle layers are responsible for radial or transversal contraction, i.e. contraction from the exterior towards the interior of the left ventricle [26];
the epicardial layers are responsible for a circumferential movement. This function can be seen using MRI tagging or echocardiography [27]. However, the feasibility and reproducibility of echocardiography remains an obstacle, even though Becker et al. [28] and Zhang et al. [29] demonstrated the positive predictive value of studying dyssynchrony using this method.

The aim of studying dyssynchrony and proposing resynchronisation therapy is to attempt to synchronise the different constituent parts of myocardial contractility and render them more mechanically effective, i.e. less energy-consuming and timed with the opening and closing of the atrioventricular and ventricular arterial valves [28, 29].

Mechanical dyssynchrony is certainly, at least in part, a dynamic process, entirely dependent on loading conditions. An isolated study at a determined time “t ” of a mechanical dyssynchrony is no doubt insufficient [30].

The echocardiographic examination could therefore proceed in stages, first of all using the simple techniques (whose limits and advantages are known) available on all ultrasound machines then, frequently, using more complex tools that require more sophisticated ultrasound equipment (for which there is an unavoidable learning curve and which have limitations). However, as echocardiography and the different tools proposed have as yet been insufficiently evaluated to date, they are not taken into account in any recommendations [1]. The recommendations of the scientific community nonetheless suggest echocardiography plays an essential role in monitoring chronic heart failure [1]. The following should be performed systematically (a prerequisite for the study of dyssynchrony):

filling and pulmonary pressure monitoring: these will always have an influence on the criteria used to measure mechanical dyssynchrony (they are a gauge of innate myocardial excitation and contraction properties but also of the constraints [parietal stress] with which it must contend);
LVEF, ventricular volume;
detection of related diseases such as valve disease.

Detection of mechanical dyssynchrony using echocardiography

Echocardiography for the detection of mechanical dyssynchrony must begin with the analysis of left ventricular kinetics using bidimensional imaging, the study examining the tilting movement of the apex, which is a two-stage movement of the apical segment of the interventricular septum (“septal flash”) which must be quantified. As previously stated (multiparametric approach), dyssynchrony should be studied in stages which we will try to describe below [31, 32]. A visual approach is insufficient and too restrictive. The temporal resolution of the human eye is not optimal. It is incapable of distinguishing anomalies unless there is a delay of at least 89ms between the movement of one wall or wall segment and the adjacent segments [33].

1st stage: detection of atrioventricular dyssynchrony

Particular attention must be paid to Doppler mitral flow shape and duration in all heart failure patients. The mitral filling time should be measured (Figure 2). A-wave integrity (if the patient is in sinus rhythm) should be checked and the mitral filling time should be more than 40% of the R-R cycle [34].

If this is not the case, atrioventricular dyssynchrony is present. This first stage is not possible if the patient presents with atrial fibrillation.

2nd stage: aortic preejection interval and interventricular dyssynchrony

Simple and essential, the aortic preejection interval (five-cavity apical incidence) and the pulmonary preejection interval (parasternal small axis) should be measured systematically. A difference of more than 40 to 45ms in these two preejection intervals is an indication of interventricular dyssynchrony (Figure 3) [8]. In the CARE-HF study, this criterion predicted resynchronisation response with a threshold value of 49.2ms [3].

The mean of three consecutive cycles should be taken. Otherwise, it should be considered that the longer the aortic preejection interval (an interval of more than 140ms is generally required), the more severe the change in left ventricular function and the higher the likelihood that left intraventricular dyssynchrony is present [35].

3rd stage: left intraventricular dyssynchrony at rest
M mode echocardiography study

In the long or short parasternal axis, the delay between peak septal contraction and peak posterior wall contraction (spatial dyssynchrony) is measured in M mode [22]. If it takes place, this delay would demonstrate the existence of a radial left intraventricular dyssynchrony (septum contracting before the posterior wall). When the anteroseptal interval or posterior wall delay is more than 130min, resynchronisation is liable to be beneficial. Described by Pitzalis et al. [22], this criterion is often very difficult to measure (severe hypokinesia or even akinesia considerably limiting feasibility) [36, 37]. This is the least reproducible and technically achievable criterion in the PROSPECT study [9]. In the RETHINQ study, it could only be analysed in one third of patients [10]. Nonetheless, it could be enlightening to use reconstructed M mode to obtain middle and apical segment views in order to quantify the septal flash. Colour tissue Doppler imaging (red/blue) may also be used but not systematically: M mode measurements remain difficult in many patients (Figure 1, Figure 2, Figure 3, Figure 4). Using M mode in four-chamber apical view, it is possible to use TM on the lateral edge of the mitral ring and to measure the delay between the foot of the QRS and mitral ring excursion maximum at its lateral edge. Pulsed transmitral Doppler is then used to measure the distance between the “foot of the QRS” and the start of the E-wave. The first measurement [33] should usually be less than 1s. If this is not the case, the lateral wall is contracting while the mitral valve is opening, signifying a systole–diastole overlap typical of temporal dyssynchrony (delay in contraction of the lateral wall) [35] (Figure 1).



Figure 1


Figure 1. 

Example of the potential value of M mode for the detection of temporal dyssynchrony (systole–diastole mismatch).

Exemple de l’intérêt potentiel du mode M pour la recherche d’un asynchronisme temporel ( mismatch systole–diastole) .

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Figure 2


Figure 2. 

Measurement of mitral filling time (pathological if less than 40% of R-R).

Mesure du temps de remplissage mitral (pathologique si moins de 40 % du R-R) et vérifier que l’onde A n’est pas tronquée et qu’il n’y a pas de fusion de E et A.

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Figure 3


Figure 3. 

Measurement of aortic and pulmonary preejection intervals (pathological if more than 40ms) (importance of calculating the mean and respecting apnoea).

Mesure et moyennage des délais prééjectionnels (pathologique si au-delà de 40 millisecondes) aortiques et pulmonaires .

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Figure 4


Figure 4. 

M mode in the study of spatial dyssynchrony. A. Colour tissue Doppler code can help identify the systolic peak shift (blue/red or red/blue transition). B. Value of reconstructed M mode for tracing an ideal line passing through the top of the left ventricle (significant radial dyssynchrony more than 130ms).

Mode M dans l’étude de l’asynchronisme spatial. A. Le mode DTI couleur peut aider mais systématiquement et (B) intérêt du M mode reconstruit pour tracer une ligne idéale sur l’ensemble de la hauteur ventriculaire gauche (asynchronisme radial significatif supérieur à 130millisecondes) .

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Tissue Doppler echocardiography study

In four-, three- and two-chamber apical views, left longitudinal intraventricular dyssynchrony (study of the contractile function of myocardial fibres from the base to the apex) will be measured.

The electrosystolic intervals correspond to the delay between the start of the QRS-wave and the S-wave peak measured using tissue Doppler (testing for spatial dyssynchrony).

This measurement is possible in pulsed DTI mode, but mainly in the basal segments. Reconstructed mode is preferable as it has the considerable advantage of combining, on the same image, the following (Figure 5):

the sequence of mechanical events (opening and closing of aortic and mitral valves);
the velocity curves measured in the septum and lateral walls from the base to the apex. These velocity curves often show systolic peaks and even a large peak during isovolumic contraction or relaxation and an almost complete absence of systolic peak. Analysis of these velocity peaks as a function of valve opening and closing times therefore appears indispensable. It could therefore be useful to switch from a “speed” imaging mode to a “displacement” or “strain” or “degree of strain” mode, while bearing in mind the advantages and disadvantages of these ways of processing the Doppler myocardial signal.



Figure 5


Figure 5. 

Study of spatial dyssynchrony using reconstructed tissue Doppler (A); shift mode (B) and strain mode (deformation) (C).

Étude de l’asynchronisme spatial en mode Doppler tissulaire reconstruit (A) ; en mode déplacement (B) et mode strain (déformation) (C) .

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In view of the results of PROSPECT and RETHINQ, a simple measurement of the electrosystolic intervals in the basal segment of the septal and lateral walls, looking for an interval exceeding 65min, appears both insufficient and often difficult and hard to reproduce when employed by ultrasonographers other than those who invented it [17]. In an observational single-centre study, the reported specificity of this criterion was 92% for the prediction of a 15% improvement in the left ventricular telesystolic volume, with a 6-month follow-up [13]. Rather than just analysing these mitral ring or basal segment mechanical phenomena, ways of analysing basal and apical segment contraction peaks, which are sources of dyssynchrony, should be found (electrical stimulation of the left ventricle in effect begins at the apex) [38, 39]. DTI colour mode allows a more global and thus more pertinent analysis of spatial dyssynchrony than pulsed tissue Doppler. DTI analysis (and associated posttreatments) can be adapted to help identify mechanical dyssynchrony. TSI mode (tissue synchronization imaging) can be used for a rapid evaluation, which is in fact parametric imaging in which delayed myocardial “movement” appears in red. This imaging mode was designed on the basis of displacement speeds [23] and has only ever been evaluated in single-centre studies. It remains based on speed, but can be used to set the goals of analysis (search for systolic or postsystolic peaks only) and can be used in triplan mode (rapid and global). This mode is particularly of value in patients with atrial fibrillation. However, when measuring speed (or displacement) it is not possible to distinguish between passive and active movements. A totally akinetic infarcted segment will be displaced passively by adjacent segments and it is highly likely that the measurement of delays in a wall with purely passive motion will not be pertinent to the prediction of resynchronisation success or failure [40].

Study of regional myocardial strain

In addition to studies of speed, it is often necessary to examine regional myocardial strain.

General principles

Strain can be studied using high imaging frequency (> 150images/s) in Doppler mode, or at lower imaging speeds (≈80images/s) in 2D-strain mode (results of speckle tracking). We will not discuss the processing method allowing the novel 2D-strain images to be obtained [41, 42, 43] although it has certain theoretical advantages including independence with regard to angle (but not the lateral resolution of the echocardiographic image which can be a limiting factor when the area in question is far from the “focal point” of the image).

Results

Strain modes (deformation) or the strain rate (the rate of deformation or gradient of the velocities in a given direction) allow regional contractility rather than displacement to be measured. Theoretically, these modes are ideal for the study of left intraventricular regional dyssynchrony. However, the signals studied can present background noise interference and therefore caution is required when they are interpreted. Several studies recently published in scientific literature emphasise the pertinence of studying left intraventricular dyssynchrony from the beginning of the strain. They analyse longitudinal (apical view) and above all radial (small axis parasternal view) strain in Doppler, above all in 2D-strain mode (which is easy to use and quite reproducible) [14, 25, 44, 45, 46, 47, 48] (Figure 5, Figure 6). Unfortunately, as with DTI in velocity mode, the studies in small series are impressive but as yet have not been validated in convincing multi-centre trials [49, 50].



Figure 6


Figure 6. 

Example of 2D-strain curves with detection of longitudinal and radial dyssynchronies and posterior and lateral delays.

Exemple de courbes de 2D-strain avec mise en évidence d’un asynchronisme longitudinal mais aussi radial avec retards postérieur et latéral .

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Study of regional volume variation in mode 3D/4D

This method requires a special probe (imaging speed rather low for the moment, less than 80images/s), good echogenicity, apnoea for three cardiac cycles and dedicated processing software (Figure 7). Using 3D/4D mode, it is possible to study regional volumes and regional variations within these volumes in the course of a cycle. A dyssynchrony index between these variations in regional volumes can thus be calculated [51]. Few studies are currently available and none of them is multi-centre. A dyssynchrony index can be calculated with a proposed threshold value of more than 8.3, making it possible to predict a favourable response to Biv restimulation therapy.



Figure 7


Figure 7. 

Example of dyssynchrony seen in 3D mode (study of regional volumes and times at which the regional volumes are minimal).

Exemple d’asynchronisme en mode 3D (étude des volumes régionaux et comparaison des temps auxquels ces volumes régionaux deviennent minimaux) .

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Evaluation of contractile reserve (and dyssynchrony)

We used pharmacological (dobutamine) or physiological (submaximal effort) stress in order to identify the myocardium likely to recover the most effective contractile function after resynchronisation therapy. The value of echocardiography under dobutamine has been established in single-centre series [31, 52, 53]. The value of stress echocardiography is less well documented [32] (Figure 8).



Figure 8


Figure 8. 

Algorithm for echocardiographic management (in our centre), for a patient with heart disease for whom resynchronisation therapy was thought to be a viable option.

Diagramme d’exploration d’une cardiomyopathie lorsqu’il est discuté une resynchronisation dans notre centre .

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Postimplantation

Mitral flow must be controlled at all costs. The A-wave must not be truncated and there should be no fusion between E- and A-waves. Left ventricular filling should also be optimised to reach 40% of the cardiac cycle without a truncated A-wave.

If this is not the case, then step by step optimisation of the pacer’s atrioventricular delay is required.

As is the case in a preimplantation setting, echocardiography can be used to control volumes, diameters and valve disease. Filling pressures may also be checked.

Optimisation of V–V delays will not be discussed in this article since, at the present time, there is little proof that would be of any interest. This was only assessed in a subgroup of nonresponding patients after 3 months of follow-up.

Conclusion

Echocardiography is an essential facet of heart failure monitoring [5]. However, the use of this imaging method to explore and quantify mechanical dyssynchrony with a view to Biv resynchronisation therapy is not currently recommended. Ten years of research in the field of dyssynchrony in echocardiography have resulted in two negative studies which have, to some extent, discredited the method [9, 10]. However, all the research conducted has led us to refine our understanding of mechanical dyssynchrony and its management. New quantification methods and generalised access to digital imagery and processing have renewed hopes that the performance of echocardiography in this field will soon improve. New criteria will no doubt be proposed and must be evaluated. While its requirements are high, PROSPECT has become an essential methodological standard [9, 16]. A study has yet to be designed that would allow a means of selecting patients for whom resynchronisation therapy is indicated, and which would lead to the publication of a revised version of the recommendations for the indications of resynchronisation in patients with systolic heart failure.

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