Echocardiography and Noninvasive Imaging in Cardiac Resynchronization

Therapy: Results of the PROSPECT (Predictors of Response to Cardiac

Resynchronization Therapy) Study in Perspective
Jeroen J. Bax, and John Gorcsan, III
J. Am. Coll. Cardiol. 2009;53;1933-1943
doi:10.1016/j.jacc.2008.11.061

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Journal of the American College of Cardiology
© 2009 by the American College of Cardiology Foundation
Published by Elsevier Inc.
CARDIAC RESYNCHRONIZATION THERAPY
Echocardiography and Noninvasive
Imaging in Cardiac Resynchronization Therapy
Results of the PROSPECT (Predictors of Response
to Cardiac Resynchronization Therapy) Study in Perspective
Jeroen J. Bax, MD, PHD,* John Gorcsan III, MD†
Leiden, the Netherlands; and Pittsburgh, Pennsylvania
Over the past decade, cardiac resynchronization therapy
(CRT) has changed the treatment of patients with end-
stage, drug-refractory heart failure. Evidence of 8 large trials
(including 4,017 patients) (1– 8) and numerous small studies
have demonstrated the benefit of CRT on heart failure
symptoms, exercise capacity, and systolic left ventricular
(LV) function. Various studies demonstrated reverse re-
modeling after CRT, with a reduction in severity of mitral
regurgitation. Moreover, recent data demonstrated a reduction
in heart failure hospitalization and mortality after CRT (6).
Various meta-analyses have subsequently been published
and confirmed these beneficial effects when data from the
available literature were pooled (9,10). Particularly, when
the 5 available randomized, controlled trials that provided
data on CRT alone were pooled (including 2,371 patients,
with 1,028 control subjects and 1,343 CRT-treated pa-
tients), a 29% reduction in all-cause mortality was shown
(16.9% mortality in the CRT-treated patients compared
with 20.7% in control subjects) (9). Similarly, a 38%
reduction in mortality due to progressive heart failure was
shown (6.7% in CRT-treated patients vs. 9.7% in control
subjects) (9). Based on the available evidence, the Amer-
ican Heart Association/American College of Cardiology/
Heart Rhythm Society guidelines consider CRT a class I
indication in patients with end-stage heart failure (New
York Heart Association [NYHA] functional class III or
IV) with left ventricular ejection fraction (LVEF) ⬍35%
and wide QRS complex (11).
A major issue confronting CRT is that, when patients are
selected according to the aforementioned criteria, approxi-
mately 30% do not have a beneficial response (12). It should
also be stressed that the patients fulfilling the selection
criteria as indicated in the preceding text are certainly not
From the *Department of Cardiology, Leiden University Medical Center, Leiden, the
Netherlands; and the †Cardiovascular Institute, University of Pittsburgh, Pittsburgh,
Pennsylvania. Dr. Bax received research grants from GE Healthcare, BMS Medical
Imaging, St. Jude, Boston Scientific, Medtronic, Edwards Lifesciences, and
Biotronik.
Manuscript received May 13, 2008; revised manuscript received October 14, 2008,
accepted November 2, 2008.
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Vol. 53, No. 21, 2009
ISSN 0735-1097/09/$36.00
doi:10.1016/j.jacc.2008.11.061
Viewpoint
equal; for example, when one looks at the plasma levels of
biomarkers such as N-terminal pro–B-type natriuretic pep-
tide, a large variance in plasma levels is noted, suggesting
that some patients have worse heart failure than others,
although all of them are in NYHA functional class III to IV,
with LVEF ⬍35%, and have wide QRS complex (6).
Cardiac dyssynchrony appears to be an important deter-
minant for response to CRT, as demonstrated in numerous
small, single-center studies (12), and can be derived from
echocardiography. An observational study to identify echo-
cardiographic predictors of response to CRT, known as
PROSPECT (Predictors of Response to CRT), was re-
cently published (13). From this study, it appeared that
echocardiographic parameters had only modest accuracy to
predict response to CRT, in contrast to the results from a
multitude of previously published studies. In this review, we
aim to explore some details of the PROSPECT study in
order to gain a better understanding and to put the
PROSPECT data in perspective with the remainder of
existing scientific literature. In addition, we will address the
contemporary and future roles of noninvasive imaging in
candidates for CRT in general.
The Problem of Responder Definition
Despite the impressive results of the large CRT trials, it has
been observed that, on an individual basis, about 30% of
patients do not respond to CRT. Inherent to this issue is the
question: “what is the precise definition of a responder?”
Indeed various end points have been used in the individ-
ual studies. These can be divided into 2 main categories:
clinical end points indicating improved clinical status
(NYHA functional class, quality-of-life score, exercise ca-
pacity expressed as 6-min walking distance) and echocar-
diographic end points indicating improved LV systolic
function or reversed LV remodeling. The occurrence of
these end points, however, was not equal. Specifically, not
all patients who exhibited a favorable response to the clinical
end point responded in a similar fashion to the echocardio-
graphic end point and vice versa. This was evaluated
1934 Bax and Gorcsan III JACC Vol. 53, No. 21, 2009
Imaging and CRT May 26, 2009:1933–43

Abbreviations recently by Bleeker et al. (14) nonresponse to CRT, substantial effort has been invested to
and Acronyms who examined 144 patients un- predict response to CRT in order to improve selection of
dergoing CRT and reported a patients who may benefit from CRT. At present, these
CRT ⴝ cardiac
resynchronization therapy favorable clinical response in selection criteria include:
70% after 6 months of CRT
LV ⴝ left • NYHA functional class III or IV despite optimized
ventricle/ventricular (defined as a reduction in NYHA
medical therapy
functional class by ⱖ1 grade),
LVEF ⴝ left ventricular • LVEF ⬍35%
compared with a salutary echo-
• QRS duration ⬎120 ms (11)
ejection fraction

NYHA ⴝ New York Heart cardiographic response of 56%

Association (defined as a reduction in LV
TDI ⴝ tissue Doppler end-systolic volume ⬎15%) in
imaging those same patients. The dis-
3D ⴝ 3-dimensional crepancy between these 2 end
points was mainly related to pa-
tients who showed clinical im-
provement but did not show LV reverse remodeling. Al-
though the precise reason for this inconsistency is unknown,
it is widely believed to be the (partial) result of a placebo
effect with device therapy resulting in subjective clinical
improvement without objective improvement in LV systolic
function or reduction in LV volumes.
If one pools the data of the 15 largest studies (15) that
have reported these end points (Tables 1 and 2), it becomes
clear that the weighted mean response rate is 66.9% for
clinical end points (3–5,14,16 –26) as compared with 56.9%
for echocardiographic end points (14,27– 40). In addition to
the above end points, it has been questioned whether the
absence of change (i.e., no deterioration) in clinical or
echocardiographic parameters should also be considered
as a positive response to CRT. Indeed, prevention of the
worsening of clinical or echocardiographic status can also be
considered a positive response to CRT.
Although the vast majority of studies have used a clinical
or echocardiographic end point, ideally one should focus on
survival as an end point. Driven by these observations of
Clinical Response After CRT (Improvement >1 NYHA Functional Class)
Table 1 Clinical Response After CRT (Improvement >1 NYHA Functional Class)
The value of cardiac dyssynchrony in response to CRT.
From both experimental and clinical imaging studies, it has
become evident that cardiac dyssynchrony is important for
response to CRT. Dyssynchrony can occur at 3 levels:
• Atrioventricular dyssynchrony
• Interventricular dyssynchrony
• Intra-(LV) dyssynchrony
The weight of current evidence favors intraventricular or
LV dyssynchrony as most associated with response to CRT.
In a summary of 24 studies using echocardiography to
predict response to CRT, only 2 studies demonstrated some
value of interventricular dyssynchrony, whereas all 24 stud-
ies showed some predictive value of LV dyssynchrony (12).
The lack of QRS duration alone to predict response could
be explained by the finding that it is related to interventric-
ular dyssynchrony, but not to LV dyssynchrony (41,42). In
general, LV dyssynchrony appears more prevalent among
patients with wider QRS complex, but this does not
necessarily translate into response to CRT. Indeed, Mol-
lema et al. (43) recently evaluated 242 heart failure patients
with wide QRS complex who underwent CRT implanta-
tion; receiver-operator characteristic curve analysis demon-
strated an optimal cutoff value for baseline QRS duration to
predict clinical response to CRT of 163 ms, which yielded
a sensitivity and specificity of 53%. It has been postulated

Patients Follow-Up Ischemic Etiology NYHA Functional QRS Duration LVEF Response Rate
Author (Ref. #) (n) (Months) (%) Class (ms) (%) (%)
Bristow et al. (5) 1,212 6 54 3.1 ⫾ 0.3 160 21 59
Higgins et al. (16) 245 6 67 2.9 ⫾ 0.7 160 ⫾ 27 21 ⫾ 6 74
Pires et al. (17) 537 6 21 3.1 ⫾ 0.3 168 ⫾ 19* 22 ⫾ 7* 62
Leon et al. (18) 359 6 46 3.1 ⫾ 0.3 164 ⫾ 22 22 ⫾ 7 ⫾70
Abraham et al. (3) 228 6 50 3.1 ⫾ 0.3 167 ⫾ 21 22 ⫾ 6 68
Ypenburg et al. (19) 191 6 56 2.9 ⫾ 0.5 163 ⫾ 30 21 ⫾ 7 76
Young et al. (4) 187 6 64 3.1 ⫾ 0.3 165 ⫾ 22 24 ⫾ 7 ⫾70
Bleeker et al. (20) 173 6 56 3.1 ⫾ 0.3 173 ⫾ 27 21 ⫾ 7 80
Bleeker et al. (21) 170 6 55 3.2 ⫾ 0.4 173 ⫾ 27 21 ⫾ 8 78
Lellouche et al. (22) 164 6 47 3.2 ⫾ 0.4 158 ⫾ 37 22 ⫾ 7 65
Bleeker et al. (14) 144 3–6 53 3.1 ⫾ 0.4 157 ⫾ 26 21 ⫾ 8 70
Molhoek et al. (23) 125 6 54 3.1 ⫾ 0.3 176 ⫾ 25 23 ⫾ 8 79
Boriani et al. (24) 121 6 63 3.1 ⫾ 0.3 175 ⫾ 22 24 ⫾ 6 69
Gasparini et al. (25) 104 ⫾9 55 3.0 ⫾ 0.7 165 ⫾ 37 27 ⫾ 7 69
Yeim et al. (26) 100 6 46 3.1 ⫾ 0.2 158 ⫾ 28 27 ⫾ 6 71
Weighted mean 6 55.4 3.1 161.4 21.9 66.9

*Approximation (patients were divided into 4 groups). Modified, with permission, from Ypenburg et al. (15).
CRT ⫽ cardiac resynchronization therapy; LVEF ⫽ left ventricular ejection fraction; NYHA ⫽ New York Heart Association.

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JACC Vol. 53, No. 21, 2009 Bax and Gorcsan III 1935
May 26, 2009:1933–43 Imaging and CRT

Echocardiographic Response After CRT (Reduction in LVESV)

Table 2 Echocardiographic Response After CRT (Reduction in LVESV)

Patients Follow-Up Ischemic Etiology NYHA Functional QRS Duration Response Rate
Author (Ref. #) (n) (Months) (%) Class (ms) LVEF (%) (%)
Yu et al. (27) 265 3–10 56 3.1 ⫾ 0.4 NA 24 ⫾ 8 55*
Bleeker et al. (14) 144 3–6 53 3.1 ⫾ 0.4 157 ⫾ 26 21 ⫾ 8 56†
Yu et al. (28) 141 3–6 48 3.1 ⫾ 0.5 NA 27 ⫾ 7/24 ⫾ 11‡ 62§
Yu et al. (29) 107 3 NA 3.2 ⫾ 0.5 NA 27 ⫾ 8 58储
Fung et al. (30) 85 3 47 3.2 ⫾ 0.7 NA 27 ⫾ 9 52储
Yu et al. (31) 76 3 49 3.0 ⫾ 0.2 NA 28 ⫾ 10 55*
Jansen et al. (32) 69 3 55 3.1 ⫾ 0.3 172 ⫾ 30 21 ⫾ 7 55†
Fung et al. (33) 60 3 47 3.2 ⫾ 0.3 150 ⫾ 27/155 ⫾ 24‡ 23 ⫾ 8/23 ⫾ 7‡ 52储
Soliman et al. (34) 60 12 42 3.0 ⫾ 0.3 170 ⫾ 27/171 ⫾ 31‡ 19 ⫾ 4/17 ⫾ 3‡ 78*
Jansen et al. (35) 57 3 53 3.1 ⫾ 0.2 169 ⫾ 28 22 ⫾ 7 65§
Yu et al. (36) 56 3 50 3.2 ⫾ 0.4 NA 26 ⫾ 9 54†
Yu et al. (37) 55 3 51 3.2 ⫾ 0.4 NA 26 ⫾ 9 53†
Murphy et al. (38) 54 6 54 3.0 ⫾ 0.3 157 ⫾ 34 27 ⫾ 8 44†
Yu et al. (39) 54 3 41 3.2 ⫾ 0.4 147 ⫾ 25/155 ⫾ 33‡ 25 ⫾ 10 57†
Zhang et al. (40) 50 3 48 3.2 ⫾ 0.4 151 ⫾ 27 27 ⫾ 9 60§
Weighted mean 4.5 50.8 3.1 160.0 24.4 56.9

Modified, with permission, from Ypenburg et al. (15). *Reduction of ⱖ15% in left ventricular end-systolic volume (LVESV); †reduction ⬎15% in LVESV; ‡responders/nonresponders; §reduction ⱖ10% in
LVESV; 储reduction ⬎10% in LVESV.
Abbreviations as in Table 1.

that patients with wider QRS complex (ⱖ150 ms) may well
respond to CRT (7), but subanalysis in patients with QRS
duration ⱖ150 ms (n ⫽ 189) yielded a sensitivity and
specificity of 54% (at an optimal cutoff value of 171 ms) to
predict clinical response (43). Moreover, as shown in Figure
1, the individualized response rates according to different
QRS durations revealed similar nonresponse rate among the
spectrum of QRS durations.
In view of the findings as noted in the previous text, many
imaging studies examined the ability of LV dyssynchrony to
Clinical response Clinical non-response
100
75
Percentage
predict the response to CRT. Helm et al. (44) demonstrated
that magnetic resonance imaging and strain analysis de-
tected substantial LV dyssynchrony in an animal model of
heart failure, which improved after biventricular pacing in
association with improved LV function. The vast majority
of studies focusing on LV dyssynchrony have been per-
formed with echocardiographic techniques to visualize LV
dyssynchrony. The most frequently used techniques include
M-mode echocardiography, tissue Doppler imaging (TDI),
strain imaging, and three-dimensional (3D) echocardiogra-
phy (Table 3). In general, these studies showed high
sensitivity and specificity (both 80% to 90%) to predict
response to CRT (12).
The PROSPECT Study
The PROSPECT study was an attempt to identify which of
several previously published markers of dyssynchrony would
forecast success of CRT using a prospective, multicenter

approach. The PROSPECT study was a nonrandomized

50
observational study that evaluated pre-defined baseline
echocardiographic dyssynchrony parameters for their ability
25
to predict clinical and echocardiographic response to CRT
(13). In that study, 426 patients were included according to
the traditional selection criteria as recommended by the
0
American Heart Association/American College of Cardiol-
120-140 140-160 160-180 180-200 >200
ogy/Heart Rhythm Society guidelines (11). The 6-month
n = 22 n = 66 n = 83 n = 47 n = 24
end points (response criteria) included a clinical composite
Baseline QRS duration (ms)
score and ⱖ15% reduction in LV end-systolic volume; the
Incidence of Response/Nonresponse According discrepancy in end points was confirmed with 69% showing
Figure 1
to QRS Width in 242 Patients Undergoing CRT clinical improvement and 56% showing echocardiographic
response.
The percentage of nonresponders is virtually the same
in the different groups (43). CRT ⫽ cardiac resynchronization therapy. Despite the intended purpose of the PROSPECT study,
the overall results were disappointing with no clear echo-
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1936 Bax and Gorcsan III JACC Vol. 53, No. 21, 2009
Imaging and CRT May 26, 2009:1933–43

TheDetect
to Most Frequently
LV Dyssynchrony
Used Echocardiographic
and Their AccuracyMeasurements
to Predict Echocardiographic Response to CRT
The Most Frequently Used Echocardiographic Measurements
Table 3
to Detect LV Dyssynchrony and Their Accuracy to Predict Echocardiographic Response to CRT

Patients Echocardiographic Dyssynchrony Sensitivity Specificity

Author (Ref. #) (n) Measurement Technique Cutoff Value (%) (%)
Pitzalis et al. (45) 20 Septal-to-posterior wall motion delay M-mode ⱖ130 ms 100 63
Marcus et al. (46) 79 Septal-to-posterior wall motion delay M-mode ⱖ130 ms 24 66
Penicka et al. (47) 49 Sum of LV and VV dyssynchrony Pulsed-wave TDI ⬎102 ms 96 77
(pulsed-wave systolic velocities)
Bax et al. (48) 25 Delay in peak systolic velocity Color-coded TDI ⱖ60 ms 76 78
(2 segments: basal septum and
lateral wall)
Notabartolo et al. (49) 49 Delay in onset of systolic velocity Color-coded TDI ⱖ110 ms 97 55
(6 basal LV segments)
Yu et al. (39) 54 Standard deviation of time to peak systolic Color-coded TDI ⱖ31.4 ms 96 78
velocities (12 LV segments)
Van de Veire et al. (50) 60 Standard deviation of time to peak systolic Tri-plane TDI ⬎33 ms 90 83
velocities (12 LV segments)
Gorcsan et al. (51) 29 Delay in peak systolic velocity (2 segments: Tissue synchronization imaging ⱖ65 ms 87 100
[antero]septal and posterior wall)
Suffoletto et al. (52) 64 Delay in peak strain (2 segments: 2D radial strain ⱖ130 ms 89 83
anteroseptal and posterior wall)
Gorcsan et al. (53) 190 Combination between longitudinal Color-coded TDI and ⱖ60 ms 88 80
and radial dyssynchrony (strain) 2D radial strain ⱖ130 ms
Marsan et al. (54) 60 Systolic dyssynchrony index ⫽ standard Real-time 3D echocardiography ⱖ5.6% 88 86
deviation of time to volume shift
(16 LV segments)

CRT ⫽ cardiac resynchronization therapy; LV ⫽ left ventricular; TDI ⫽ tissue Doppler imaging; VV ⫽ interventricular; 2D ⫽ 2-dimensional; 3D ⫽ 3-dimensional.

cardiographic dyssynchrony measure that was highly pre-
dictive of CRT in this setting. The complicated list of
echocardiographic dyssynchrony parameters, including
M-mode, pulsed-wave Doppler, and tissue Doppler indexes,
that were studied with their cutoff values is shown in Table 4.
The PROSPECT study results were in contrast to a
multitude of previously published echocardiographic studies
from many international centers that reported much more
favorably on prediction of response to CRT (Table 3) (12).
Unfortunately, some individuals regarded the PROSPECT
study as a definitive study because of its multicenter design
and concluded that echocardiographic markers of dyssyn-
Main Results From the PROSPECT Study
Table 4 Main Results From the PROSPECT Study
chrony were of no clinical value. However, we have learned
subsequently of several methodological and procedural
problems with the PROSPECT study that are worthy of
reviewing.
The PROSPECT Study Results in Perspective and
How to Improve?
The main question is: why did the PROSPECT study
results demonstrate only a modest value of echocardiogra-
phy to predict response to CRT, in contrast to previously
published studies? Although the reported echocardiographic

Echocardiographic Dyssynchrony % Echocardiograms Intraobserver CV Interobserver CV Sensitivity Specificity

Measurement Technique Cutoff Value Assessable (%) (%) (%) (%)
Septal-to-posterior wall motion delay M-mode ⱖ130 ms 72 24.3 72.1 64 52
LV pre-ejection interval: delay between Pulsed-wave Doppler ⱖ140 ms 95 3.7 6.5 72 44
onset QRS and onset LV ejection
Interventricular delay: difference Pulsed-wave Doppler ⱖ40 ms 92 NA NA 60 54
between left and right pre-ejection
intervals
LV filling time in relation to cardiac Pulsed-wave Doppler ⱖ40% 85 NA NA 41 74
cycle length (pulsed-wave Doppler)
Delay in peak systolic velocity Color-coded TDI ⱖ60 ms 67 NA NA 53 69
(2 segments: basal septum and
lateral wall)
Delay in onset of systolic velocity Color-coded TDI ⱖ110 ms 81 NA NA 68 34
(6 basal LV segments)
Standard deviation of time to peak Color-coded TDI ⱖ31.4 ms 50 11.4 33.7 78 31
systolic velocities (12 LV segments)

Data from Chung et al. (13).

CV ⫽ coefficient of variation; PROSPECT ⫽ Predictors of Response to Cardiac Resynchronization Therapy; other abbreviations as in Table 3.

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JACC Vol. 53, No. 21, 2009 Bax and Gorcsan III 1937
May 26, 2009:1933–43 Imaging and CRT

Issuesthe
From Related
PROSPECT
to theStudy
Modest
andPredictive
Potential Results
Improvements for Future Studies
Issues Related to the Modest Predictive Results
Table 5
From the PROSPECT Study and Potential Improvements for Future Studies

PROSPECT Study What Is Needed?

Patient selection 20.2% had LVEF ⬎35% Larger studies limited to patients with LVEF ⱕ35% and
37.8% had LVEDD ⬍65 mm dilated LV (LVEDD ⱖ60 or 65 mm)
Technical issues Nonassessability of echocardiographic measurements Better training for data acquisition and analysis
(highest for M-mode and TDI)
Low interobserver reproducibility of echocardiographic Do we need better technology to assess LV dyssynchrony
measurements (highest variation for M-mode and TDI) (e.g., 3D approaches, strain-based echocardiographic
approaches, role of magnetic resonance imaging)?
Pathophysiological issues Influence of pathophysiological issues not included in PROSPECT Need for integrated approach including assessment of:
Influence of scar tissue on nonresponse Scar tissue (location and transmurality)
LV dyssynchrony versus LV lead positioning LV dyssynchrony (extent and location)
Influence of venous anatomy versus LV lead positioning Venous anatomy (distribution and suitability for leads)
What is the role of the various imaging techniques
(echocardiography, magnetic resonance imaging,
nuclear cardiology, computed tomography)?

LVEDD ⫽ left ventricular end-diastolic diameter; LVEF ⫽ left ventricular ejection fraction; TDI ⫽ tissue Doppler imaging; 3D ⫽ 3-dimensional; other abbreviations as in Tables 3 and 4.

dyssynchrony data predicting response to CRT were prom-
ising, they could be criticized for being single-center studies
with small sample sizes, except for 1 study by Gorcsan et al.
(53), which included 190 patients and was performed in 2
different centers.
M-Mode Tracing of a Patient With Previous Infarction,
Figure 2 Without Septal Excursion (Akinesia), Prohibiting
Assessment of the Septal-to-Posterior Wall Motion Delay
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Various potential issues related to the unexpected results
reported in the PROSPECT study are summarized in Table 5.
Patient selection. Most of the patients in small single-
center studies were carefully selected, with inclusion of only
the most severe heart failure patients. In the PROSPECT
study, 20.2% of patients had an LVEF more than 35% and
37.8% had an LV end-diastolic dimension ⬍65 mm,
suggesting inclusion of less severe heart failure patients.
This is a particularly important confounding variable in the
PROSPECT study because reverse LV remodeling was one
of the primary end points. In other words, an LV that was
not dilated to begin with cannot reverse remodel in response
to CRT. Accordingly, larger studies in heart failure patients
with severely depressed LVEF (ⱕ35%) and LV dilation
(LV end-diastolic diameter ⬎60 or 65 mm) are needed.
Technical issues. A large percentage of nonassessable
echocardiographic data were encountered, both for TDI and
M-mode imaging, with feasibility yields ranging from
50% to 81% (as compared with 92% to 95% for the
2-dimensional echocardiography data). Moreover, the in-
terobserver variability of M-mode and TDI measurement
was large, indicating lack of standardized data acquisition
and analysis. Better training and education might improve
the assessability of echocardiographic (M-mode and TDI)
parameters, and also reduce interobserver variability. For
example, an improvement in the rigor of TDI data analysis
is needed, such as size and placement of the regions of
interest, to reduce interobserver variability. Also, TDI
analysis is based on comparison in timing of peak systolic
velocities of different cardiac regions; at times, not 1 but
multiple peaks are observed during systole, and a clear and
uniform agreement on the selection of peaks that are used to
calculate LV dyssynchrony is needed (55,56). Moreover,
some studies have included peak systolic velocities occurring
after aortic valve closure post-systolic velocities in the
calculation of cardiac dyssynchrony, whereas other studies
excluded post-systolic signals, and consensus on this issue is
currently lacking.
1938 Bax and Gorcsan III JACC Vol. 53, No. 21, 2009
Imaging and CRT May 26, 2009:1933–43

228

AS P

Baseline 6 months

Figure 3 Patient Example of 2D Speckle Tracking Strain Assessment

(Left) The 2-dimensional (2D) strain images and segmental curves in a patient before cardiac resynchronization therapy. The segmental time-strain curves (color-coded)
represent the 6 myocardial segments (light blue ⫽ septal; yellow ⫽ anteroseptal [AS]; red ⫽ anterior; green ⫽ lateral; purple ⫽ posterior [P]; and dark blue ⫽ inferior).
From these curves, the maximum time difference in peak systolic strain between 2 segments can be determined (in this patient, 228 ms). Resynchronization after
6 months of cardiac resynchronization therapy is shown in the right panel.

Figure 4 Tri-Plane Tissue Synchronization Imaging in a Patient With Dilated Cardiomyopathy Showing Severe LV Dyssynchrony

Using a tri-plane probe, the 2-, 3-, and 4-chamber views are simultaneously acquired. This 3-dimensional assessment of dyssynchrony displays mechanical activation
times in colors. The orange-yellow color indicates late activation of the inferior and posterior regions as compared with the remainder of the myocardium (green). The
polar map shows the timing from QRS to peak systolic velocity in each of 12 segments that are analyzed (bottom right); the inferior and posterior segments (yellow)
show the latest mechanical activation. LV ⫽ left ventricular.

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JACC Vol. 53, No. 21, 2009 Bax and Gorcsan III 1939
May 26, 2009:1933–43 Imaging and CRT

A B

Figure 5 Parametric Polar Maps Derived From Real-Time 3-Dimensional Echocardiography

Color-coding (blue indicating early activation and orange-red late activation) represents the time needed to reach the minimum systolic volume, showing that the inferior
and posterior left ventricular regions are the latest activated before cardiac resynchronization therapy (A). Six months after cardiac resynchronization therapy (B), the
overall green color indicates absence of regions with delayed activation.

Figure 6 Phase Analysis on Gated Myocardial Perfusion SPECT Permits Assessment of LV Dyssynchrony

(A) Shows data from a patient without left ventricular (LV) dyssynchrony. The homogeneous phase angle distribution (non-normalized) is illustrated by a homogeneous
color-coding scale (polar map format, left) and a narrow and highly peaked histogram (right). Phase angle reflects timing of conduction within the cardiac cycle (0° to
360°). (B) Shows data from a patient with extensive LV dyssynchrony. The heterogeneous phase angle distribution (non-normalized) is reflected by a heterogeneous
color-coding scale (polar map format, left) and a broad and moderate peaked histogram (right). SPECT ⫽ single-photon emission computed tomography. Reproduced,
with permission, from Henneman et al. (60).

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1940 Bax and Gorcsan III JACC Vol. 53, No. 21, 2009
Imaging and CRT May 26, 2009:1933–43

forecast the response to CRT, including magnetic resonance

y = -0.4369 x + 0.550
(58) and nuclear imaging techniques (59,60) (Fig. 6).
80
r = 0.91, P < 0.05 Pathophysiological issues. It has been shown that scar
tissue in the region where the LV pacing lead is positioned
60
may reduce the effect of CRT (61,62); of note, the precise
Change in LV end-systolic volume (%)

extent of scar tissue throughout the wall (transmurality) that

40 would result in nonresponse is not yet clear. In addition, it
has been shown that the total extent of scar tissue in the LV
20 is important: too great a scar tissue limits response to CRT
(Fig. 7) (63). Most imaging techniques have been used for
the assessment of scar tissue, although contrast-enhanced
0
magnetic resonance imaging may be preferred since its high
spatial resolution permits precise delineation of transmural-
-20 ity of scar tissue (Fig. 8).
The position of the LV pacing lead is also important;
-40 preliminary studies have indicated that positioning the LV
0,00 0,50 1,00 1,50 2,00
Total scar burden

The Total Scar Burden Versus the

A
Figure 7
Change in LVESV After 6 Months of CRT

A clear relation between the 2 parameters existed. Patients with extensive scar
tissue showed virtually no improvement in left ventricular end-systolic volume
(LVESV) after cardiac resynchronization therapy (CRT). LV ⫽ left ventricle.
Reproduced, with permission from Ypenburg et al. (63).

Furthermore, TDI data were obtained using instruments

from 3 ultrasound vendors without standardization of frame
rates, and 3 different software programs were used for offline
data analysis. It seems apparent in retrospect that these
technical differences introduced confounding variables that
likely affected the PROSPECT study results. When the
PROSPECT study began, technological development of
offline software for dyssynchrony analysis was relatively new, B
and improvements by all 3 vendors have occurred subse-
quently to reduce variability.
In addition, improvement in technology for assessment of
LV dyssynchrony is needed. In patients with extensive
infarction, both M-mode imaging and TDI fail (to some
extent) to provide optimal information on LV dyssyn-
chrony; the septum is frequently a flat line on M-mode
imaging (Fig. 2), and TDI provides only information on
myocardial velocities, which does not permit differentiation
between passive motion and active deformation. In this
respect, strain analysis (providing information on active
deformation) may be preferred, and novel 2-dimensional
strain techniques are promising (Fig. 3). This difficulty has
recently been highlighted in various articles, proposing strain as
the preferred marker for LV dyssynchrony assessment (55,56). Location and Quantification of
Figure 8
In addition, 3D echocardiographic imaging may be pre- Scar Tissue With Contrast-Enhanced MRI
ferred since it provides optimal information on LV dyssyn-
Contrast-enhanced magnetic resonance imaging (MRI) has excellent spatial
chrony throughout the entire LV (Figs. 4 and 5) (54,57). resolution and may be the preferred technique for assessment of scar tissue.
Still, it is clear that LV dyssynchrony is important in the (A) A patient with transmural infarction in (part of) the lateral wall, the inferior
wall, and the septum (the white tissue, arrow). (B) Subendocardial scar forma-
prediction of response to CRT. Not only have echocardio-
tion in a patient with a previous inferior infarction (arrow indicates scar
graphic techniques shown this, but other imaging modali- formation).
ties have also reported the value of LV dyssynchrony to
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JACC Vol. 53, No. 21, 2009 Bax and Gorcsan III 1941
May 26, 2009:1933–43 Imaging and CRT

Figure 9 Noninvasive Visualization of the Venous Anatomy Is Possible With Multislice CT

(A) An example of 64-slice computed tomography (CT) in a patient without coronary artery disease and a large variety of cardiac veins. (B) 64-slice CT in a patient with
previous infarction (the scar tissue is visible) and minimal cardiac veins. CS ⫽ coronary sinus; GCV ⫽ great cardiac vein; LMV ⫽ left marginal vein; PIV ⫽ posterior
interventricular vein; PVLV ⫽ posterior vein of the left ventricle.

lead outside of the region of latest activation on echocar- Conclusions

diography resulted in poor response to CRT (38,64). In this
perspective, it may be important to noninvasively assess the Mechanical LV dyssynchrony appears to be an important
venous anatomy before CRT implantation to decide pathophysiological feature that is improved by CRT, and
whether (accessible) veins are present in the target region or this improvement is related to LV reverse remodeling and
whether a surgical approach with epicardial LV lead place- favorable clinical outcomes. A large body of published
ment may be preferred. The feasibility of noninvasive evidence from a multitude of independent scientific insti-
assessment of venous anatomy with multislice CT has been tutions from around the world have demonstrated promise
demonstrated recently, and results indicated that poor for echocardiographic measures of LV dyssynchrony to
venous anatomy can be encountered in patients with previ- predict response to CRT. Although the results of the
ous infarction (Fig. 9) (65). Moreover, coregistration of
multislice computed tomography and 3D dyssynchrony
maps may provide the required information (66).
All of these aforementioned issues can potentially influ-
ence the response to CRT and may have been more
prominently present in the PROSPECT study population,
as compared with the carefully selected populations in the
small, single-center studies.
While issues concerning the study population and tech-
nology can be at least partially resolved in the future,
pathophysiological factors that prevent response to CRT
cannot be significantly altered. It appears increasingly im-
portant to integrate the information on LV dyssynchrony
(site of latest mechanical activation), the location and
transmural extent of infarction, and the venous anatomy
before CRT implantation. Based on this integrated infor-
mation, it will be possible to determine whether the patient Integrated Information on Dyssynchrony,
Figure 10 Scar, and Region of Latest Mechanical
has a high or low likelihood of response to CRT (Fig. 10); Activation May Improve Response to CRT
this may be more realistic rather than focusing on LV
Various factors for prediction of response to cardiac resynchronization therapy
dyssynchrony parameters only, aiming to derive at precise
(CRT) are important, including left ventricular (LV) dyssynchrony, scar tissue in
cutoff values to predict response to CRT. One can even the region where the LV pacing lead is positioned, the total extent of scar in
foresee that based on an integrated approach, the focus will the LV, and whether the LV lead is positioned in the site of latest mechanical
activation. Based on these factors, one can distinguish patients with a low and
become to identify nonresponders with high precision,
high likelihood of response to CRT. LVEF ⫽ left ventricular ejection fraction;
which may be the most important issue from a clinical NYHA ⫽ New York Heart Association.
perspective.
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1942 Bax and Gorcsan III
Imaging and CRT
PROSPECT study were modest in comparison with results
from many single-center studies, one should not conclude
that the PROSPECT study is more correct because of its
multicenter design. Clearly, patient selection, technical
factors with echocardiographic data acquisition and analysis,
and pathophysiological issues are significant confounding
variables that need to be considered when interpreting the
PROSPECT study results. CRT is undeniably a beneficial
therapy for a large number of heart failure patients who are
selected properly. The PROSPECT study taken in perspec-
tive has taught us some valuable lessons regarding the
complexity of echocardiographic dyssynchrony analyses and
other factors that influence patient response to CRT.
Refinements in the technical aspects of data acquisition and
analysis along with a greater understanding of pathophysi-
ology will continue to add benefit to the care of CRT
patients.
Reprint requests and correspondence: Dr. Jeroen J. Bax, Depart-
ment of Cardiology, Leiden University Medical Center, Albinus-
dreef 2, 2333 ZA Leiden, the Netherlands. E-mail: j.j.bax@
lumc.nl.
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Key Words: heart failure y cardiac resynchronization therapy y cardiac
dyssynchrony y tissue Doppler imaging.
 Echocardiography and Noninvasive Imaging in Cardiac Resynchronization
Therapy: Results of the PROSPECT (Predictors of Response to Cardiac
Resynchronization Therapy) Study in Perspective
Jeroen J. Bax, and John Gorcsan, III
J. Am. Coll. Cardiol. 2009;53;1933-1943
doi:10.1016/j.jacc.2008.11.061
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