STATE-OF-THE-ART PAPER
Cardiac Resynchronization Therapy
Part 1—Issues Before Device Implantation
Jeroen J. Bax, MD*,*,
Theodore Abraham, MD, FACC ,
S. Serge Barold, MD, FACC ,
Ole A. Breithardt, MD ,
Jeffrey W.H. Fung, MD||,
Stephane Garrigue, MD, PhD¶,
John Gorcsan, III, MD, FACC#,
David L. Hayes, MD, FACC**,
David A. Kass, MD,
Juhani Knuuti, MD, PhD,
Christophe Leclercq, MD, PhD,
Cecilia Linde, MD, PhD,
Daniel B. Mark, MD, PhD, FACC||||,
Mark J. Monaghan, PhD¶¶,
Petros Nihoyannopoulos, MD, FRCP, FACC, FESC***,
Martin J. Schalij, MD*,
Christophe Stellbrink, MD and
Cheuk-Man Yu, MD||
* Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
Johns Hopkins University, Baltimore, Maryland
University of South Florida, Tampa, Florida
University of Klinikum Mannheim, Mannheim, Germany
|| The Chinese University of Hong Kong, Hong Kong, China
¶ Hopital Cardiologique du Haut-Leveque, Pessac, France
# University of Pittsburgh, Pittsburgh, Pennsylvania
** Mayo Clinic, Rochester, Minnesota
Turku PET Center, University of Turku, Turku, Finland
Hopital Pontchaillou, Rennes, France
Karolinska University Hospital, Stockholm, Sweden
|||| Duke Clinical Research Institute, Durham, North Carolina
¶¶ King’s College Hospital, London, United Kingdom
*** Hammersmith Hospital, London, United Kingdom
Stadtische Kliniken Bielefeld, Bielefeld, Germany
Manuscript received April 19, 2005;
revised manuscript received September 19, 2005,
accepted September 19, 2005.
* Reprint requests and correspondence: Dr. Jeroen J. Bax, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands. (Email: jbax{at}knoware.nl).
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Abstract
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Cardiac resynchronization therapy (CRT) has been used extensively over the last years in the therapeutic management of patients with end-stage heart failure. Data from 4,017 patients have been published in eight large, randomized trials on CRT. Improvement in clinical end points (symptoms, exercise capacity, quality of life) and echocardiographic end points (systolic function, left ventricular size, mitral regurgitation) have been reported after CRT, with a reduction in hospitalizations for decompensated heart failure and an improvement in survival. However, individual results vary, and 20% to 30% of patients do not respond to CRT. At present, the selection criteria include severe heart failure (New York Heart Association functional class III or IV), left ventricular ejection fraction <35%, and wide QRS complex (>120 ms). Assessment of inter- and particularly intraventricular dyssynchrony as provided by echocardiography (predominantly tissue Doppler imaging techniques) may allow improved identification of potential responders to CRT. In this review a summary of the clinical and echocardiographic results of the large, randomized trials is provided, followed by an extensive overview on the currently available echocardiographic techniques for assessment of LV dyssynchrony. In addition, the value of LV scar tissue and venous anatomy for the selection of potential candidates for CRT are discussed.
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Abbreviations and Acronyms
| | CMR = cardiovascular magnetic resonance | | CRT = cardiac resynchronization therapy | | LV = left ventricle/ventricular | | LVEF = left ventricular ejection fraction | | MIRACLE = Multicenter InSync Randomized Clinical Evaluation study | | MSCT = multislice computed tomography | | NYHA = New York Heart Association | | TDI = tissue Doppler imaging | | TSI = tissue synchronization imaging |
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Cardiac resynchronization therapy (CRT) has changed the treatment of patients with end-stage, drug-refractory heart failure. To date, eight large randomized, clinical trials in CRT have been completed (1–8). A summary of these trials, with a total of 4,017 patients, is provided in Table 1. The inclusion criteria in these trials were:
- Severe heart failure, New York Heart Association (NYHA) functional class III and IV
- Depressed systolic left ventricular (LV) function, LV ejection fraction (LVEF) <35%
- Wide QRS complex: >120 ms with interventricular conduction disorder
The Cardiac Resynchronization-Heart Failure (CARE-HF) study is the only study that, to some extent, has included the presence of LV dyssynchrony in the inclusion criteria.
In these large trials, the most frequently used primary end points mainly reflect the functional status (6-min walk test, NYHA functional class, quality of life score, and peak O2) and should be considered clinical end points. The vast majority of studies demonstrated improvement in 6-min walking distance, NYHA functional class, and quality of life score. In addition, the majority of studies that evaluated peak O2 reported an improvement in this parameter after CRT.
Few studies have focused on morbidity and mortality. In particular, the recent CARE-HF study has focused primarily on morbidity and mortality (6). Inconsistency on the reduction in hospital admissions has been reported. While a reduction in hospitalizations was observed in the Multisite Simulation in Cardiomyopathies (MUSTIC) and Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trials (2,3), this was not the case in the CONTAK-Cardiac Defibrillator (CONTAK-CD) and MIRACLE-Implantable Cardioverter Defibrillator trials (4,8). The Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial demonstrated a reduction in the composite end point of all-cause mortality or hospitalization during 16 months follow-up (5). The CARE-HF study subsequently demonstrated a clear survival benefit after CRT as compared to optimized medical therapy (6).
Secondary end points in the studies were predominantly echocardiographic measurements including:
- LV systolic function, LVEF,
- LV reverse remodeling, LV volumes,
- Mitral regurgitation
In these large randomized trials, detailed information on echocardiographic data is not consistently available, but detailed echocardiographic studies have been performed. In general, LV systolic function improved, LV reverse remodeling occurred, and mitral regurgitation decreased. However, the extent of improvement in LVEF and reduction in LV volumes varied substantially among studies.
Based on the available trials, the current American College of Cardiology/American Heart Association/North American Society of Pacing and Electrophysiology guidelines state that CRT is beneficial in patients with heart failure, severe systolic LV dysfunction, and wide QRS complex (level of evidence class IB). Although the results are indeed promising, analysis of individual responses revealed that 20% to 30% of patients do not respond to CRT (3,9). Accordingly, emphasis has shifted towards selection of potential responders to CRT, before device implantation. Before discussing the identification of responders, the definition of a responder should be addressed.
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Who is a responder to CRT?
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Small studies have initially used invasive methods to assess acute hemodynamic response to CRT. Long-term response (usually assessed at three to six months of CRT) is mainly evaluated by clinical or echocardiographic parameters (Table 2). The relationship between acute hemodynamic response and chronic outcomes is still not entirely clear.
Clinical parameters are subjective and mainly reflect symptoms; a substantial placebo effect may be present in 40% of individuals (3). Still, these are the criteria that are traditionally used to evaluate patients with heart failure, and may be most relevant from a patient perspective. The ultimate clinical end points include a reduction in hospitalization and mortality rate.
Echocardiographic parameters may be more objective. Improvements in LV systolic function (mainly expressed as LVEF) have been reported in most studies, but the absolute increase in LVEF varied substantially among studies (3,6,8). Reverse LV remodeling (indicated by a decrease in LV systolic and diastolic diameters and volumes) has been reported consistently in CRT studies and often used as an indicator of response (2,3,6,8). Indeed, molecular changes in the lateral wall of the LV such as increased stress kinase levels may decrease after CRT. Whether these changes contribute to the reverse LV remodeling or are merely a result of the reverse remodeling is yet unclear. Echocardiography has also been used to demonstrate improvements in inter- and intraventricular dyssynchrony (10).
Clinical non-responders have also been reported when correlated with echocardiographic results. Yu et al. (11) used a 15% improvement in LV end-systolic volume index after CRT and demonstrated non-response in 13 of 30 (43%) patients. Moreover, clinical and echocardiographic response to CRT may not always appear simultaneously, and patients who respond clinically may not exhibit reverse LV remodeling and vice versa. It appears that more patients exhibit improvement in clinical parameters as compared to echocardiographic markers. This discrepancy may even further complicate the definition of response to CRT.
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QRS duration to predict response to CRT
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The response to CRT was initially considered to result in part from resynchronization of interventricular dyssynchrony (dyssynchrony between the left and right ventricle). Thus, patients with interventricular dyssynchrony were selected for CRT. This selection was based on the QRS duration, because this parameter is considered to reflect interventricular dyssynchrony. Indeed, Rouleau et al. (12) demonstrated a good relation between interventricular dyssynchrony (assessed by tissue Doppler imaging [TDI]) and QRS duration. Accordingly, patients with wide QRS were considered candidates for CRT. In general, studies used QRS duration >120 to 130 ms as a selection criterion. The initial studies required the presence of a left bundle branch block pattern on the electrocardiogram, whereas more recent studies also included patients with non-specific interventricular conduction delay (a poorly defined entity) or even right bundle branch block pattern. The beneficial effect of CRT on symptoms, exercise capacity, systolic LV function, and hospitalization rate was demonstrated in these patients with wide QRS complex, as outlined in the preceding text (Table 1). In addition, data from the Pacing Therapies in Congestive Heart Failure (PATH-CHF) II trial demonstrated that the benefit of CRT was most pronounced in patients with QRS duration >150 ms (as compared to patients with QRS duration 120 to 150 ms) (13). These observations tend to support the use of the QRS duration for patient selection. However, careful analysis of the individual patients in many CRT studies demonstrated that 20% to 30% of the patients failed to respond to CRT, despite prolonged QRS duration. In particular, Reuter et al. (14) evaluated 102 patients undergoing CRT and reported non-response in 18% of patients. These observations prompted Molhoek et al. (15) to analyze the precise value of the QRS duration to predict response to CRT. Their study included 61 patients, and 45 (74%) responded to CRT. The QRS duration at baseline before pacing was similar between the responders and non-responders (179 ± 30 ms vs. 171 ± 32 ms; p = NS). However, a significant shortening in QRS duration after six months of CRT was observed only in responders. Receiver operating characteristic curve analysis showed that a reduction in QRS duration >10 ms had a high sensitivity (73%) with low specificity (44%) (Fig. 1) in prediction of responders. Conversely, a reduction in QRS duration >50 ms was highly specific (88%) but not sensitive (18%) to predict response to CRT. Comparable findings were recently reported by Lecoq et al. (16).
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Figure 1 Receiver operating characteristic curve analysis on the change in QRS duration after six months of cardiac resynchronization therapy (CRT) demonstrated an optimal sensitivity of 58% and 56% (using a cutoff value of 30 ms) to predict response to CRT. Adapted from Molhoek et al. (15).
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It has subsequently been suggested that intraventricular dyssynchrony may predict response to CRT more accurately (10). In this respect, studies using TDI demonstrated that patients with intraventricular dyssynchrony had a high likelihood of a positive response to CRT (10). Bleeker et al. (17) evaluated the relation between QRS duration and LV dyssynchrony (assessed by TDI) in 90 patients with severe heart failure; LVEF <35%; and narrow (<120 ms), intermediate (120 to 150 ms), or wide (>150 ms) QRS complexes. Substantial LV dyssynchrony on TDI was present in 27%, 60%, and 70% of patients, respectively. When QRS duration was considered as a continuous variable, no relation between QRS duration and LV dyssynchrony could be demonstrated (Fig. 2). Ghio et al. (18) confirmed the absence of LV dyssynchrony in 48% of patients with an intermediate (120 to 150 ms) QRS complex and in 28% of patients with a wide (>150 ms) QRS complex. These observations indicate that patients with a wider QRS complex have a higher likelihood of LV dyssynchrony, although 30% of patients with wide (>150 ms) QRS complex lack LV dyssynchrony. This 30% may partially explain a similar percentage of non-responders in the large trials. These observations have resulted in many echocardiographic studies evaluating different echocardiographic parameters to detect LV dyssynchrony and predict response to CRT.
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Figure 2 The QRS duration does not relate with the extent of left ventricular (LV) dyssynchrony as assessed with tissue Doppler imaging. Adapted from Bleeker et al. (17).
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Echocardiographic selection of responders to CRT: Role of interventricular dyssynchrony
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Echocardiography is the most practical approach to evaluate dyssynchrony and predict response to CRT. Initial studies have focused on assessment of interventricular (left-right) dyssynchrony to predict response. Interventricular dyssynchrony can be evaluated by pulsed-wave Doppler echocardiography assessing the extent of interventricular mechanical delay defined as the time-difference between left and right ventricular pre-ejection intervals; a delay of 40 ms or more has been proposed as a marker of interventricular dyssynchrony (10). Bordachar et al. (19), however, reported that interventricular dyssynchrony was not related to hemodynamic improvement during CRT.
Tissue Doppler imaging has also been used to assess interventricular dyssynchrony (11,20,21). Three studies used TDI to compare the delay between peak systolic velocity of the right ventricular free wall and the LV. Although Penicka et al. (21) suggested that assessment of interventricular delay by TDI contributed to the prediction of response to CRT, this was not confirmed by two different studies where TDI was used (11,20). Bax et al. (20) evaluated 80 patients undergoing CRT and demonstrated a similar extent of interventricular dyssynchrony in the 59 responders and the 21 non-responders (47 ± 34 ms vs. 49 ± 29 ms; p = NS). Yu et al. (11) demonstrated that interventricular dyssychrony was not predictive of response to CRT in 54 patients undergoing CRT. Thus, most evidence suggests that interventricular dyssynchrony is not useful in the prediction of response to CRT.
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Echocardiographic selection of responders to CRT: Role of LV dyssynchrony on M-mode, two-dimensional echocardiography, and TDI
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A variety of echocardiographic techniques have been suggested for the assessment of LV dyssynchrony and prediction of response to CRT. These techniques include M-mode assessment, two-dimensional echocardiography using phase imaging or intravenous contrast, TDI, and potentially three-dimensional echocardiography (10). Tissue Doppler imaging is the most extensively tested technique, and different methods have been proposed, including pulsed-wave TDI, color-coded TDI, tissue tracking, displacement mapping, strain and strain rate imaging, and, most recently, tissue synchronization imaging (TSI). A comprehensive summary of the merits of the different techniques to predict response to CRT is provided in Table 3.
M-mode echocardiography.
Using an M-mode recording from the parasternal short-axis view (at the level of the papillary muscles), the septal-to-posterior wall motion delay can be obtained, and a cutoff value of 130 ms or more was proposed as a marker of intraventricular dyssynchrony. Pitzalis et al. (22) evaluated 20 patients and reported a sensitivity and specificity of 100% and 63%, respectively, to predict response to CRT. In addition, the authors recently demonstrated the prognostic value of the septal-to-posterior wall motion delay (23). However, this parameter is often difficult to obtain. Rose et al. (24) evaluated the feasibility of obtaining this parameter in the patients of the CONTAK-CD database. A clear definition of the systolic deflection of both the septal and posterior wall was possible in only 45% of 79 patients. Moreover, the septal-to-posterior wall motion delay did not correlate with LV reverse remodeling. Most importantly, the sensitivity and specificity to predict response (both clinical and echocardiographic) were 24% and 66%. These findings were similar in patients with ischemic and dilated cardiomyopathy.
Two-dimensional echocardiography.
The first use of two-dimensional echocardiography was that of a semiautomatic method for endocardial border delineation (25). The degree of LV dyssynchrony was quantified in two-dimensional echocardiographic sequences from the apical four-chamber view, focusing on the septal-lateral relationships. Computer-generated regional wall movement curves were compared by a mathematical phase analysis, based on Fourier transformation. The resulting septal-lateral phase angle difference is a quantitative measure for intraventricular (dys)synchrony. Using this approach, patients with extensive LV dyssynchrony between the septum and lateral wall exhibited an immediate improvement in hemodynamics after CRT. The second approach utilized echo contrast (Optison, Mallinckrodt, Hazelwood, Missouri) to optimize LV border detection (26). With the improved LV border detection, regional fractional area changes were determined and plotted versus time, yielding displacement maps. From these maps, the LV dyssynchrony between the septum and lateral wall was determined. The authors observed an acute reduction in LV dyssynchrony after biventricular pacing, which correlated with an acute increase in LVEF. No studies on the two-dimensional techniques for prediction of long-term outcome have been published.
TDI, strain, and strain rate imaging.
Tissue Doppler imaging measures the velocity of longitudinal cardiac motion and allows comparison of timing of motion in relation to electrical activity (QRS complex). Different parameters can be derived, and the most frequently used include the peak systolic velocity, the time to onset of systolic velocity, and the time to peak systolic velocity.
The TDI measurements can be obtained directly using pulsed-wave TDI and using color-coded TDI, which needs post-processing. With pulsed-wave TDI, only one region can be interrogated at a time making the procedure time-consuming and precludes comparison of segments simultaneously. Because measurements are influenced by differences in heart rate, loading conditions and respiration measurements that are not simultaneous may be less meaningful. In addition, the timing of peak systolic velocity is often difficult to identify, resulting in imprecise information on LV dyssynchrony. There is limited evidence of pulsed-wave TDI to predict response to CRT. Two studies have demonstrated a relation between LV dyssynchrony on pulsed-wave TDI and improvement in symptoms and/or LVEF after CRT (27,28), but prediction of response was not addressed. Bordachar et al. (19) showed that LV dyssynchrony assessed by pulsed-wave TDI correlated with an improvement in cardiac output and reduction in mitral regurgitation after CRT. Penicka et al. (21) used pulsed-wave TDI (with an integration of interventricular and LV dyssynchrony) and reported a sensitivity of 96% with a specificity of 77% to predict response to CRT.
Eight studies have used color-coded TDI to assess LV dyssynchrony and predict outcome (Table 3) (11,20,29–34). From these color-coded images, TDI tracings can be obtained by post-processing, and the majority of studies have used time to peak systolic velocity to assess LV dyssynchrony. Initially, investigators focused on the four-chamber view to identify LV dyssynchrony by color-coded TDI (Fig. 3). Velocity tracings were derived from the basal septal and lateral segments, and the septal-to-lateral delay was measured. It was shown that a delay  60 ms was predictive of acute response to CRT (30). Subsequently, a four-segment model was applied, which included four basal segments (septal, lateral, inferior, and anterior) (20). It was shown that a delay 65 ms allowed prediction of response to CRT. Using this cutoff value, sensitivity/specificity for prediction of clinical improvement (defined by an improvement in NYHA functional class and 6-min walking distance) were both 80% whereas sensitivity/specificity for LV reverse remodeling (defined as a 15% reduction in LV end-systolic volume) were both 92%. In addition, patients with LV dyssynchrony 65 ms had a favorable prognosis after CRT.
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Figure 3 Color-coded four-chamber tissue Doppler image (upper left). Post-processing yields velocity tracings (right); severe left ventricular dyssynchrony is present as indicated by the delay in the peak systolic velocity of the septum (yellow curve) as compared to the lateral wall (green curve).
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The extensive studies by Yu et al. (11,29,31) have used a 12-segment model. Tracings were derived from 12 segments, and an LV dyssynchrony index was derived from the standard deviation of all 12 time intervals demonstrating that a dyssynchrony index 31 ms yielded a sensitivity and specificity of 96% and 78% to predict LV reverse remodeling (11). In general, prediction of response to CRT based on time to peak systolic velocity (using a varying number of segments) yields a high sensitivity (ranging from 76% to 97%) and specificity (ranging from 55% to 92%) (Table 3).
Seven studies have used tissue tracking, strain, and/or strain rate imaging (11,33–38). Tissue tracking (GE Vingmed, Horten, Norway) provides a color-coded display of myocardial displacement, allowing for easy visualization LV dyssynchrony and the region of latest activation. Sogaard et al. (34) pioneered this approach and demonstrated that the number of segments with delayed longitudinal contraction was related to the improvement in LVEF during CRT.
Strain and strain rate analysis is performed by off-line analysis of the color-coded tissue Doppler images. Strain analysis allows direct assessment of the extent and timing of myocardial deformation during systole and is expressed as the percentage of segmental shortening or lengthening in relation to its original length (10). The main advantage over TDI is that strain analysis allows differentiation between active systolic contraction and passive motion. This is important in patients with ischemic cardiomyopathy with the presence of scar tissue. Breithardt et al. (35) showed that CRT reversed the pathologic septal-lateral strain relationships and reduced the incidence of early systolic pre-stretch in the late activated wall and of post-systolic shortening. However, no study with strain or strain rate imaging has so far reported on the actual prediction of response to CRT (Table 3), except for Yu et al. (11), who demonstrated that strain rate imaging could not predict LV reverse remodeling. Despite the technical advantages of the strain imaging, the technique has not become routine practice in the evaluation of patients considered for CRT. The main limitations are the time-consuming aspect of the technique, the high operator dependency, and the moderate reproducibility. Only one direct comparison between TDI and strain rate imaging has been reported in 54 patients undergoing CRT (11). Left ventricular dyssynchrony on TDI was predictive of LV reverse remodeling, but strain rate imaging failed to predict response to CRT (11).
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TSI to assess LV dyssynchrony
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A recent addition to the tissue Doppler approach to quantify LV dyssynchrony has been the automated color-coding of time to peak longitudinal velocities. This color-coding of temporal velocity data is superimposed on the routine two-dimensional echocardiographic images to provide visual mechanical information on the anatomical regions. Tissue synchronization imaging (GE Vingmed) (38–40) is a signal-processing algorithm of the tissue Doppler data to automatically detect peak positive velocity and then color-code the time to peak velocities in green for normal timing, yellow-orange for moderate delay, and red for severe delays in peak longitudinal velocity (Fig. 4). Interval start time is manually fine-tuned to begin with aortic valve opening to exclude isovolumic contraction velocity and extended to rapid filling (E-wave) to include post-systolic LV dyssynchrony; TSI color-coding is then used to guide placement of 7 x 15 mm oval regions of interest in the basal and mid-segments from apical views. Regions of interest are localized where the color-coding of timing is most representative for the anatomical segment for time-velocity curve analysis. Although the color-coding information is very useful, it is considered important to continue to use the time-velocity tracings to correctly identify the peak velocities for LV dyssynchrony analysis. Left ventricular dyssynchrony can be defined as difference in time to peak velocity of opposing walls: inferoseptal to lateral wall (four-chamber view), anterior to inferior wall (two-chamber view), and anteroseptal to posterior wall (long-axis view). In a pilot series of 29 patients, TSI was assessed before CRT, and acute response (defined as an immediate increase in LV stroke volume by 15% or more) was observed in 21 patients (39). Differences in baseline TSI time to peak velocity of opposing LV walls (three views average) were greater in acute responders than non-responders: 120 ± 148 ms versus 35 ± 153 ms (p < 0.05). When delays between individual walls were compared, dyssynchrony between the anteroseptal and posterior wall (assessed from the apical long-axis view) had the greatest ability to separate acute responders from non-responders after CRT. A cutoff value of 65 ms had a sensitivity and specificity of 87% and 100%, respectively, to predict acute response to CRT (39). The cutoff value of 65 ms is in agreement with other results (20) using color-coded TDI. In addition, a recent study by Yu et al. (40) used TSI in 56 patients to predict LV reverse remodeling after three months of CRT, and a sensitivity of 87% with a specificity of 81% was demonstrated.
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Figure 4 Tissue synchronization imaging, four-chamber view. (Left) The color represents timing: green = normal timing; red = severe delay. Color-guided visual identification of the site of latest activation facilitates sample-placement to derive the tissue Doppler imaging (TDI) velocity tracings. In this patient, the earliest activation (green) is in the lateral wall, and the latest activation is in the lateral wall (red); the TDI velocity tracings (right) confirm the delay between the septum and lateral wall.
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Recent technological enhancements include multiplane TSI imaging to keep frame rates high with three-dimensional reconstruction of color-coded temporal LV activation; imaged in the time-domain, this allows actual four-dimensional information. Examples of four-dimensional TSI in a normal individual and a patient with LV dyssynchrony are demonstrated in Figures 5 and 6. Angle-corrected tissue Doppler data for color-coded temporal activation, known as Dyssynchrony Imaging (Toshiba, Tokyo, Japan), also have the potential to provide radial dyssynchrony data that may be additive to dyssynchrony analysis of longitudinal velocities alone. In 38 patients undergoing CRT, Dohi et al. (38) showed a sensitivity of 95% with a specificity of 88% to predict acute response to CRT using radial dyssynchrony.
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Figure 5 Four-dimensional tissue synchronization imaging (TSI) of a normal individual. From the different views (left), a three-dimensional impression of the left ventricle is reconstructed (middle). The entire three-dimensional image of the left ventricle is green indicating no dyssynchrony. Post- processing allows the display of the different segments in a polar map format (right) to further facilitate identification of the site of latest activation.
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Figure 6 Four-dimensional tissue synchronization imaging (TSI) of a patient with left ventricular dyssynchrony. From the different views (left), a three-dimensional impression of the left ventricle is reconstructed (middle). The region of latest activation is indicated in red. Post-processing yields the polar-map format (upper right) indicating in red the site of latest activation (anteroseptal), and further calculations can be performed (lower right) to further quantify the extent of left ventricular dyssynchrony using different parameters.
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Three-dimensional echocardiography to assess LV dyssynchrony
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Three-dimensional echocardiography has evolved from a technique based on reconstruction of multiple two-dimensional scan planes to an almost real-time methodology. Left ventricular volumes and LVEF can be assessed with high accuracy (41). In the context of LV dyssynchrony, analysis of regional function in the time-domain is important (10), and a series of plots is obtained representing the change in volume for each segment (usually 16 or 17 segments) throughout the cycle (Fig. 7). With synchronous contraction of all segments, each segment would be expected to achieve the minimum volume at almost the same point in the cardiac cycle. In LV dyssynchrony, dispersion exists in the timing of the point of minimum volume for each of the segments. The degree of dispersion reflects the severity of LV dyssynchrony (42).
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Figure 7 Real-time three-dimensional full volume analysis of regional left ventricular function showing (top left) the reconstructed left ventricular cast and the bulls-eye display (bottom left) of the 16 segments. Changes in regional volume (color-matched) for each of the 16 segments is displayed in the upper right. The anteroseptal and septal segments (light blue and green) show poor function and significant delay in achieving a minimum volume compared to other segments. A first derivative display of the regional volume curves is shown in the lower right panel and also demonstrates significant dispersion in the timing of minimal regional volume (indicated by the zero crossing points).
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Parametric "polar-map" displays (of the three-dimensional data) of the timing of LV contraction have been developed to facilitate interpretation of data. This methodology examines regional LV contraction at approximately 3,000 points over the endocardial surface rather than in 16 or 17 segments. Color-coding is used to identify the region/site of latest activation, and this is potentially useful for electrophysiologists to select the optimal LV lead position. Examples of parametric polar-map images (of the three-dimensional data) pre- and post-CRT are displayed in Figure 8. Zhang et al. (43) used three-dimensional echocardiography in 13 patients who had previously received CRT; when CRT was withheld, significant LV dyssynchrony occurred, associated with a decrease in LVEF. Currently, no extensive data are available on the prediction of response to CRT using three-dimensional echocardiography.
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Figure 8 Parametric polar-map displays (lower left and lower right panels) of left ventricular dyssynchrony of the real-time three-dimensional images; blue indicates early activation, red indicates late activation. Left ventricular dyssynchrony is present before cardiac resynchronization therapy (CRT) in the anteroseptal region (red, lower left panel); almost complete resynchronization has occurred after CRT, with disappearance of "red" regions (lower right).
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Other factors related to response: Venous anatomy and scar tissue
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Besides LV dyssynchrony, other factors are important for success of CRT. In particular, the venous anatomy is important. Considerable variability exists in the venous system (44) as well as variability in the nomenclature used to designate specific coronary veins. The authors evaluated venous anatomy by retrograde venography in 129 consecutive patients referred for implantable cardioverter defibrillator implantation. In 5 (4%) patients coronary sinus cannulation failed, and in 38 (29%) visualization was suboptimal and/or venograms were incomplete. In the remaining 86 patients, the anterior interventricular vein and middle cardiac vein could be visualized in 99% and 100% of patients, respectively. The veins (posterior or left marginal veins) between these two veins are mostly used for LV lead placement in CRT. Only one prominent vein was present in 51% of patients, two veins in 46% of patients, whereas more than two veins were present in only 2% of patients. When patients would be considered for CRT only in the presence of the posterior veins, 55% would be acceptable. When patients would be considered for CRT in the presence of the posterior or the left marginal veins, 99% would be acceptable. Ideally, venous anatomy should be assessed non-invasively, at the outpatient clinic, to determine whether a transvenous approach is feasible, or whether a (minimal invasive) surgical approach should be used for LV lead implantation. The feasibility of multislice computed tomography (MSCT) to visualize the venous anatomy was recently demonstrated (45). The variability in venous anatomy was confirmed, and findings were in line with previous invasive observations; MSCT allowed not only precise determination of coronary sinus and its tributaries, but also assessment of distances between veins and ostial size of the coronary sinus. An example of an MSCT depicting venous anatomy is demonstrated in Figure 9.
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Figure 9 Noninvasive multislice computed tomography of the venous anatomy. (Left) Three-dimensional volume rendered reconstruction. (Right) Multiplanar curved reconstruction (MPR) of the coronary sinus (CS). Indicated on the three-dimensional reconstruction (left) are the CS, the posterior interventricular vein (PIV), the posterior vein of the left ventricle (PVLV), and the great cardiac vein (GCV). LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle.
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Although information on venous anatomy is needed, it is really the integrated information on the site of latest activation (maximum LV dyssynchrony) and venous anatomy that determines the approach for LV lead implantation (transvenous versus surgical). Accordingly, it would be desired for example to fuse the three-dimensional TSI images (Figs. 5 and 6) with the MSCT images (Fig. 9), in order to co-registrate electromechanical delays with venous anatomy.
Another factor that is important for success of CRT is whether scar tissue is present in the region of latest activation (where the LV lead should be positioned). Currently, no solid data on this issue are available. One anecdotal report, however, demonstrated that initial response to CRT was reversed after acute infarction in the territory of the LV lead (46). It would, therefore, be of potential interest to evaluate non-invasively, before CRT implantation, whether the target region for LV lead positioning contains viable tissue or whether scar tissue is present. Various techniques are available, including nuclear imaging techniques, echocardiographic techniques, or cardiovascular magnetic resonance (CMR). Routine resting single-photon emission computed tomography imaging with a technetium-99m-labeled tracer would provide the requested information, as indicated in Figure 10, showing a large defect in the inferior and posterolateral regions, indicating scar tissue. Contrast-enhanced CMR may eventually provide the optimal information, because it allows precise depiction of the extent, and transmurality of scar tissue (Fig. 11).
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Figure 10 Resting single-photon emission computed tomography images (using technetium-99m tetrofosmin) of a patient with a previous inferoposterolateral infarction. A severe defect in tracer uptake is visible on the mid-ventricular short-axis slice (SA) (left) in the inferior and posterolateral regions, which is confirmed on the horizontal long-axis (HLA) (middle) and vertical long-axis (VLA) (right) projections.
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Figure 11 Contrast-enhanced cardiovascular magnetic resonance short-axis slices illustrating the presence and transmural extent of scar tissue. (Left) Non-transmural scar tissue in the posterolateral wall as indicated by the hyperenhanced (white) region. (Right) Transmural scar formation in the posterolateral region.
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Conclusions
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In large clinical trials, the beneficial effect of CRT has been demonstrated. On an individual basis, however, 20% to 30% of patients still do not respond to CRT. Observational echocardiographic studies have clearly demonstrated that the presence of LV dyssynchrony is an important factor determining response to CRT, whereas interventricular dyssynchrony appears of less importance. Various studies using different echocardiographic approaches have subsequently aimed at prediction of response to CRT, and the available literature suggests that TDI using 2-, 4-, or 12-segment models of LV dyssynchrony may represent the best method to predict response to CRT. Careful analysis of the literature also reveals the limitations of published studies. The number of patients is small in most studies, a lack of consensus exists in assessment of response (in particular clinical parameters vs. echocardiographic parameters), the measurements of LV dyssynchrony are different among studies, and direct comparisons between LV dyssynchrony parameters to predict response are virtually absent. The Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study is underway to examine if prospectively defined echocardiographic parameters of systolic dyssynchrony are able to predict a favorable response to CRT, and the latter includes both clinical composite end points and LV reverse remodeling (47). Still, from the existing evidence, it appears mandatory to expand current guidelines for patient selection for CRT, and to include assessment of LV dyssynchrony.
In addition to LV dyssynchrony, information on venous anatomy and the presence of scar tissue may further optimize response to CRT, but further studies are needed to fully appreciate the clinical importance of these issues.
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Footnotes
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Dr. Abraham receives honoraria from GE, Guidant, Medtronic, St. Jude and receives research support from Guidant; Dr. Barold received lecture fees from receives research support from Guidant; Dr. Barold received lecture fees from Medtronic; Dr. Breithardt has been a consultant for Medtronic and Guidant and has research affiliations with Medtronic, Guidant, and GE Vingmed; Dr. Hayes is on the advisory board of Guidant Inc. and has been a speaker for Guidant Inc., Medtronic Inc., St. Jude Medical, and ELA Medical, and has received royalties from Blackwell Futura; Dr. Gorcsan received research grant support from GE, Toshiba, Siemens, Medtronic, and St. Jude; Dr. Kass has been a consultant for Guidant Inc.; Dr. Mark has been a consultant and received grants from Medtronic, Inc. Dr. Monaghan has received support from Philips, GE, Siemens, Guidant, Medtronic, and Accusphere; Dr. Schalij is on the advisory board of Guidant and has received research grants from Medtronic, Guidant, and St. Jude; Dr. Stellbrink is a sponsored investigator for Guidant, Medtronic, St. Jude, and Biotronik and is also an advisor to Guidant and Biotronik; Dr. Nihoyannopoulos received research grants and consultant fees from Medtronic.
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References
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Abstract
Who is a responder...