1058

Comparison of Efficacy of Reverse Remodeling and Clinical

Improvement for Relatively Narrow and Wide QRS Complexes
After Cardiac Resynchronization Therapy for Heart Failure
CHEUK-MAN YU, M.D., JEFFREY WING-HONG FUNG, M.R.C.P., CHI-KIN CHAN, M.R.C.P.,
YAT-SUN CHAN, M.R.C.P., QING ZHANG, B.M., M.M., HONG LIN, B.M., M.M.,
GABRIEL W.K. YIP, M.R.C.P., LEO C.C. KUM, M.R.C.P., SHUN-LING KONG, B.N., M.N.,
YAN ZHANG, B.M., and JOHN E. SANDERSON, M.D.
From the Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong

Kong, Hong Kong; and Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong

Efficacy of CRT for Mildly Prolonged QRS. Introduction: Cardiac resynchronization therapy
(CRT) has been shown to reverse left ventricular (LV) remodeling and improve symptoms in heart failure
patients with wide QRS complexes; however, its role in patients with mildly prolonged QRS complexes is
unclear. This study investigated if CRT benefited patients with mildly prolonged QRS complexes >120 to
150 ms and explored if the severity of systolic asynchrony determined such a response.
Methods and Results: Fifty-eight patients (age 66 11 years, 66% male) who had undergone CRT
were studied prospectively. Of these patients, 27 had QRS duration between 120 and 150 ms (group A),
and 31 had QRS duration >150 ms (group B). Tissue Doppler echocardiography and clinical assessment
were performed at baseline and 3 months after CRT. Both groups had significant reduction of LV volume
and increased ejection fraction, +dP/dt, and sphericity index (all P < 0.05). These improvements were
greater in group B and were explained by the higher prevalence of systolic intraventricular asynchrony.
Significant reverse remodeling (reduction of LV end-systolic volume >15%) was evident in 46% of group A
patients and 68% of group B patients. Improvement in clinical endpoints was observed in both groups (all
P < 0.01), although the changes in metabolic equivalent and New York Heart Association functional class
were greater in group B. In both groups, systolic asynchrony index (TS -SD) was the most important predictor
of reverse remodeling (r = 0.78, P < 0.001) and was the only independent predictor in the multivariate
model ( = 1.80, confidence interval = 2.18 to 1.42, P < 0.001); QRS duration was not. A predefined
TS -SD value >32.6 ms had a sensitivity of 94% and specificity of 83% to predict reverse remodeling.
Improvement of intraventricular asynchrony after CRT was evident only in responders (P = 0.01).
Conclusion: Improvement of LV remodeling and clinical status is evident after CRT in heart failure
patients with QRS duration >120 to 150 ms. These responders are closely predicted by the severity
of prepacing intraventricular asynchrony but not QRS duration. (J Cardiovasc Electrophysiol, Vol. 15,
pp. 1058-1065, September 2004)

biventricular pacing, heart failure, echocardiography, pacemakers, Doppler echocardiography

Introduction
Cardiac resynchronization therapy (CRT) in the form of
biventricular pacing is a useful nonpharmacologic therapy
for patients having chronic heart failure with electromechan-
ical delay.1 The improvement in symptoms and functional
capacity has been shown consistently in multicenter clini-
cal trials.2-4 Left ventricular (LV) reverse remodeling also
has been observed to be an important response to therapy,
characterized by a reduction of LV volume as long as pacing
is maintained5 and an increase in ejection fraction.5,6 Pre-
vious multicenter trials mostly included patients with very
Address for correspondence: Cheuk-Man Yu, M.D., Division of Cardiol-
ogy, Department of Medicine and Therapeutics, Prince of Wales Hospital,
The Chinese University of Hong Kong, Hong Kong. Fax: 852-2637-3852;
E-mail: cmyu@cuhk.edu.hk
Manuscript received 23 November 2003; Accepted for publication 27
February 2004.
doi: 10.1046/j.1540-8167.2004.03648.x
prolonged QRS complex duration (at least 150 ms),2 al-
though a QRS duration between 120 to 150 ms has been
included in other studies.4,7,8 The current recommendation
for CRT in heart failure patients includes New York Heart
Association (NYHA) functional class III or IV symptoms
with ECG evidence of prolonged QRS duration >130 ms.9
However, most of the early studies recruited mainly patients
with very prolonged QRS duration, and there is very little
experience with patients with mildly prolonged QRS com-
plexes (>120150 ms). It is unknown whether this partic-
ular group of patients will respond to CRT with LV re-
verse remodeling or clinical improvement and, if so, what
the response rate will be. Therefore, the current study was
conducted (1) to investigate whether LV reverse remodel-
ing and improvement of systolic function occur after CRT
in advanced heart failure patients with mildly prolonged
QRS complex duration (>120150 ms); (2) to determine
whether clinical symptoms and exercise capacity improve
in these patients; and (3) to compare these changes to those
occurring in patients with typically wide QRS complexes
(>150 ms).
 Yu et al. Efficacy of CRT for Mildly Prolonged QRS 1059

CD). The AV interval was optimized by Doppler echocar-

TABLE 1
diography as previously described.11
Clinical Characteristics of Patients with Mildly Prolonged (Group A) and
Wide (Group B) QRS Complexes
Echocardiography
Group A Group B
(N = 27) (N = 31) 2 and P Value
Standard echocardiography, including Doppler studies,
was performed (System 5 or Vivid 5, Vingmed-General Elec-
Age (years) 64 11 68 12 P = NS tric, Horten, Norway). LV dimensions and ejection frac-
Male/female gender (%) 68/32 73/27 2 = 0.09, P = NS tion were measured by two-dimensionally guided M-mode
New York Heart Association 89:11 61:39 2 = 7.06, P = 0.03 method. LV volumes and ejection fraction were assessed by
functional class III:IV (%)
ECG Simpsons equation using the apical four-chamber view. Car-
QRS duration (ms) 134 14 172 22 P < 0.001 diac output was assessed by pulsed-wave Doppler echocar-
PR interval (ms) 205 47 205 51 P = NS diography. The rate of pressure rise in systole (+dP/dt) was
QRS pattern (%) estimated from the continuous-wave Doppler mitral regur-
Left bundle branch block 15 87 2 = 24.6, P < 0.001
Intraventricular conduction 40 13
gitation velocity curve.12 The severity of midsystolic mitral
delay regurgitation was assessed by the percentage jet area relative
Normal 45 to left atrial size in the apical four-chamber view. At least
Etiology of heart failure (%) three consecutive beats of sinus rhythm were measured and
Ischemic/nonischemic 48/52 36/64 2 = 0.95, P = NS the average value taken.
Optimal AV internal (ms) 105 34 95 23 P = NS
Medication (%)
TDI was performed using apical views for long-axis mo-
Diuretic 100 100 < 0.01, P = NS
2 tion of the ventricles as previously described.13-15 Two-
Angiotensin-converting 93 100 2 = 1.22, P = NS dimensional echocardiography with TDI color imaging was
enzyme inhibitor or ARB performed with a 2.5- or 3.5-MHz phased-array transducer.
Beta-blocker 70 81 2 0.50, P = NS Gain settings, filters, and pulse repetition frequency were ad-
Spironolactone 41 35 2 = 0.08, P = NS justed to optimize color saturation, and sector size and depth
Nitrate 44 48 2 = 0.12, P = NS
were optimized for the highest possible frame rate. At least
Digoxin 19 23 2 = 0.47, P = NS
Antiarrhythmic drug 30 23 2 = 0.24, P = NS three consecutive beats were stored, and the images were
digitized and analyzed off-line (EchoPac 6.3.6, Vingmed-
ARB = angiotensin receptor blocker.
General Electric). Myocardial pulsed-Doppler velocity pro-
file signals were reconstituted off-line from the TDI color
Methods images that provided regional myocardial velocity curves.13
From the apical four-chamber, two-chamber, and long-axis
Patients views, a six-basal and six-midsegmental model was obtained
Fifty-eight patients (mean age 66 11 years, 38 males) in the LV, namely, septal, lateral, anteroseptal, posterior, an-
with NYHA functional class III (n = 43) or IV (n = 15) terior, and inferior segments at both basal and mid levels.5,13
heart failure, LV ejection fraction <40%, current optimal Myocardial sustained systolic velocity (SM ) and time to peak
medical therapy, and ECG evidence of prolonged QRS >120 SM (TS ) were measured. For TS , the beginning of the QRS
ms were recruited for biventricular pacing therapy (Table 1). complex was used as the reference point.13 To assess sys-
Among these patients, 31 had QRS duration between 120 and tolic synchronicity, the standard deviation of TS of the 12 LV
150 ms (group A), and 27 had QRS duration >150 ms (group myocardial segments (TS -SD) in each patient was calculated
B). Alternation of treatment during the study period was as the systolic asynchrony index as previously described,5
avoided. Serial investigations were performed before and 3 where a greater value represents more severe systolic asyn-
months after CRT. The studies included echocardiography chrony. The mean SM of six LV basal segments was calculated
with tissue Doppler imaging (TDI), 6-minute hall walk test, as an index of systolic function.16 To perform TDI in addition
treadmill exercise protocol to estimate metabolic equivalents to routine echocardiography, another 10 minutes was required
(MET), and Minnesota Living with Heart Failure Question- for image acquisition and another 20 minutes was used for
naire for quality of life. The study protocol was approved by off-line analysis. The time required for AV optimization was
the local ethics committee, and written informed consent was about 15 minutes. The averages of at least three consecutive
obtained from all patients. beats were used for comparison. Interobserver and intraob-
server variability has been confirmed to be <5%.5 Valida-
Biventricular Device Implantation tion of TDI has been performed in physical models,17 animal
models14,18 and human subjects19 and found to be accurate in
Atrio-synchronized biventricular pacemakers were im-
assessing regional velocity and timing of cardiac events.13
planted as previously described.1,5,10 The LV pacing lead
was inserted via a transvenous approach through the coronary Statistical Analysis
sinus into the lateral or posterolateral cardiac vein. Forty pa-
tients received an Attain system (model 2187, 4189, or 4191 For comparison of parametric variables before and after
[side-wire lead] or model 4193 [over-the wire], Medtronic CRT, paired sample t-test was used. Comparison of changes
Inc., Minneapolis, MN, USA), and 18 received the Easytrak in clinical and echocardiographic parameters between the two
over-the-wire lead (model 4512, Guidant Inc., St. Paul, MN, groups was performed by unpaired t-test. Correlation anal-
USA). Fifty-four patients received a biventricular pacemaker ysis was used to compare the relationship between baseline
(InSync, InSync III, Medtronic, Inc., Minneapolis, MN, or systolic asynchrony and degree of reverse remodeling and the
Contak TR, Giudent, Minneapolis, MN), and 4 received a gain in ejection fraction after pacing. All data are expressed as
biventricular cardiac defibrillator (InSync ICD or Contak mean SD. P < 0.05 is considered statistically significant.
1060 Journal of Cardiovascular Electrophysiology Vol. 15, No. 9, September 2004

Results in 8 (28%) in group B. In group A, 12 patients (46%) had

Among the 58 patients, 27 had QRS duration >120 to
150 ms (group A), and 31 had QRS duration >150 ms
(group B). There was no difference with regard to age, gender,
and etiology of heart failure between group A and group B
(Table 1). With regard to QRS pattern, a left bundle branch
block pattern was present in the majority of group B patients,
whereas intraventricular conduction delay was more preva-
lent in group A patients ( 2 = 24.6, P < 0.001). In 9 patients
in group A, the QRS pattern was deemed to be normal by
the primary care physician because it was only widened and
did not have any features typical of the other two patterns.
There was no difference in the programmed AV interval opti-
mized by Doppler echocardiography between the two groups.
At the end of 3 months, all patients were being maintained
in the biventricular pacing mode. Four patients died before
3-month follow-up was complete, so repeat assessment was
not performed.
LV Reverse Remodeling and Cardiac Function
Baseline echocardiographic parameters were not different
between group A and group B, with a comparable degree of
LV enlargement and systolic dysfunction (Table 2). At the
end of 3 months, LV end-diastolic and end-systolic volumes
were decreased significantly in both groups, with a signifi-
cant increase in LV end-diastolic and end-systolic sphericity
indices (Table 2). For systolic function, LV ejection fraction
(P 0.001) and +dP/dt (P = 0.01) were increased in both
groups, whereas cardiac output and mean SM were signif-
icantly increased only in group B (P = 0.02 and 0.03, re-
spectively). Mitral regurgitation was reduced in both groups.
LV filling time was significantly shortened only in group B
(P = 0.045). Response to LV reverse remodeling was defined
as a reduction of LV end-systolic volume (LVVs) >15% as
previously described.20-22 When the degree of LV reverse
remodeling was compared further in the two groups, LVVs
was reduced >15% in 19 patients (68%), enlarged >15%
in 1 (4%), and relatively stable (between 15% and +15%)
significant reverse remodeling, 3 (12%) had a significant in-
crease in LVVs, and 11 (42%) had a stable LVVs (group
A vs group B, 2 = 2.98, P = NS). Reductions of LVVs
(13.5 21.7 vs 30.9 27.0%, P = 0.01) and LV end-
diastolic volume (7.0 19.0 vs 22.0 23.4%, P = 0.01),
and gains in LV ejection fraction (5.5 7.3 vs 11.0 12.1%,
P = 0.04) and +dP/dt (162 232 vs 453 380, P = 0.03)
were significantly greater in group B than in group A.
Clinical Endpoints
Prior to CRT, baseline clinical assessments were not dif-
ferent between the two groups, except that more patients in
group B were in NYHA class IV (Table 1). All clinical end-
points were improved 3 months after CRT in both groups,
including the 6-minute hall walk distance (P = 0.008 and
P < 0.0001), quality-of-life score (both P < 0.001), maximal
metabolic equivalent achieved (P = 0.009 and P < 0.001),
and NYHA class (P = 0.001 and P < 0.001; Table 2). How-
ever, improvements in metabolic equivalent (+0.8 1.0 vs
+1.7 1.3 METs, P = 0.03) and NYHA class (0.52
0.60 vs 1.09 0.61, P = 0.004) were significantly greater
in group B than in group A. This trend also was present for
the gain in 6-minute hall walk distance (54 69 vs 79 69
m) and quality-of-life score (16 18 vs 24 19),
although they were not significant.
Systolic Synchrony
Irrespective of QRS duration, there is a very close re-
lationship between the severity of systolic asynchrony and
improvement of cardiac remodeling. The LV systolic asyn-
chrony index (TS -SD) is an excellent predictor of reduction
in LVVs (r = 0.78, P < 0.001) and gain in LV ejection frac-
tion (r = 0.73, P < 0.001). TS -SD was significantly higher
in responders than nonresponders to LV reverse remodel-
ing (P < 0.001; Fig. 1). TS -SD was reduced significantly in
responders (P = 0.01) but was increased in nonresponders
(P = 0.001; Fig. 1). Further analysis revealed that responders

TABLE 2
Comparison of Clinical and Echocardiographic Parameters Before and After Biventricular Pacing for Three Months in Patients with Mildly Prolonged
(Group A) and Wide (Group B) QRS Complexes

Group A Group B
Baseline 3 Months P Value Baseline 3 Months P Value

6-minute hall walk distance (m) 345 101 399 74 0.008 278 104 357 86 <0.001
Quality-of-life score 31.0 23.0 15.5 14.9 <0.001 42.5 29.1 20.4 20.2 <0.001
Metabolic equivalents 3.6 1.2 4.4 1.5 0.009 3.1 0.9 4.8 1.6 <0.001
New York Heart Association class 3.0 0.5 2.5 0.7 0.001 3.5 0.6 2.4 0.5 <0.001
Ejection fraction (%) 28.4 7.3 33.9 9.7 0.001 26.0 12.9 37.0 12.5 <0.001
Left ventricular end-systolic volume 127 64 110 63 0.004 147 68 98 56 <0.001
Left ventricular end-diastolic volume 173 81 160 78 0.04 193 67 148 67 <0.001
Mitral regurgitation (%) 31 21 24 13 0.05 32 14 18 13 0.02
Cardiac output (L/min) 2.5 1.0 2.8 1.0 NS 2.7 0.6 3.1 0.5 0.02
+dP/dt (mmHg/s) 680 205 842 283 0.01 507 112 960 396 0.01
Sphericity index: end-systole 1.75 0.29 1.92 0.45 0.01 1.73 0.14 1.95 0.34 0.005
Sphericity index: end-diastole 1.57 0.20 1.70 0.30 0.01 1.60 0.15 1.76 0.27 0.01
Isovolumic contraction time (ms) 120 40 95 29 0.008 133 36 98 32 <0.001
Isovolumic relaxation time (ms) 115 41 127 46 NS 134 40 145 36 NS
Left ventricular filling time (ms) 373 143 445 143 0.06 367 136 440 87 0.046
Mean SM (cm/s) 3.08 0.97 3.22 1.03 NS 2.80 1.50 3.40 1.15 0.03
Mean SM = mean peak myocardial systolic velocity of the six left ventricular basal segments.

Figure 1. Comparison of the standard deviation of time to peak myocardial
systolic velocity of the 12 left ventricular segments (T S -SD) before and 3
months after biventricular pacing in responders and nonresponders to re-
verse remodeling. Responders had significantly higher baseline T S -SD than
nonresponders, which was decreased after biventricular pacing. In contrast,
the nonresponders had significantly increased T S -SD despite therapy.
had delayed peak basal lateral wall contraction over the basal
anteroseptal wall (P < 0.001), indicating systolic asynchrony.
This difference was abolished after biventricular pacing
(Fig. 2). In contrast, anteroseptal-lateral asynchrony was not
evident in nonresponders before pacing and was unaffected
by CRT (Fig. 2). Figure 3 shows examples of a patient from
each group who had significant improvement of systolic
synchronicity after CRT. Both patients were responders to
reverse remodeling.
The relationship between QRS duration and reverse re-
modeling was examined further. Baseline QRS duration was
only a weak predictor of reduction in LVVs (r = 0.35,
Figure 2. Histogram showing the time to peak myocardial systolic velocity
(T S ) at the basal anteroseptal (BAS) and basal lateral (BL) segments of the
left ventricle before and 3 months after biventricular pacing in responders
and nonresponders to reverse remodeling. Responders had significant delay
in the BL wall over the BAS wall before pacing, and the difference were
abolished after biventricular pacing by prolonging the T S in the BAS seg-
ment. In contrast, there is no septolateral asynchrony in the nonresponders
at baseline, whereas pacing has no effect on overall synchronicity as both
the BAS and BL segments were delayed to a similar extent.
Yu et al. Efficacy of CRT for Mildly Prolonged QRS 1061
P = 0.01) and was unable to predict the gain in ejection frac-
tion (r = 0.28, P = 0.06). Similarly, the change in QRS dura-
tion was a relatively weak predictor of reduction in LVVs (r =
0.43, P = 0.008) and was an even worse predictor for ejection
fraction (r = 0.31, P = 0.05). When TS -SD, baseline QRS
duration, and its change after CRT were compared for their
power to predict reduction in LVVs in a stepwise multivariate
regression model, the only independent predictor of reverse
remodeling was TS -SD ( = 1.80, CI = 2.18 to 1.42,
P < 0.001). The predictive value of baseline ( = 0.11, P
= NS) or change in QRS duration ( = 0.06, P = NS) was
lost.
The ability of TS -SD to predict LV reverse remodeling
after CRT was examined further according to a cutoff point
of 32.6 ms, which was derived from the +2 SD from the
mean of 88 normal subjects as previously described.22 The
overall sensitivity to predict reverse remodeling was 94%,
with specificity of 83%, positive predictive value of 88%, and
negative predictive value of 90%. These values were 83%,
86%, 83%, and 86%, respectively, in group A and 100%,
78%, 88% and 90%, respectively, in group B.
Discussion
The present study supports the beneficial role of CRT in
heart failure patients with mildly prolonged QRS complexes
of 120 to 150 ms. Although the degree of reverse remodeling,
improvement of cardiac function, and clinical improvement
were greater in patients with wide QRS complexes >150 ms,
significant improvement of these endpoints was observed in
those with mildly prolonged QRS duration after CRT for
3 months. The proportion of patients with significant LV re-
verse remodeling response appears to be smaller in the group
with mildly prolonged QRS duration. This is explained by
the lower prevalence of significant intraventricular mechani-
cal asynchrony in the latter group. Nonetheless, it is important
to stress that intraventricular asynchrony is observed in nearly
half of patients with mildly prolonged QRS duration, which
is the only independent predictor of response. Improvement
of intraventricular asynchrony after CRT was evident only in
the responders to reverse remodeling.
LV reverse remodeling after CRT is a favorable event that
has been described consistently in the recent literature.5,6,20,23
Previous studies usually recruited patients with very pro-
longed QRS duration >150 ms.2 Even in other studies that
included patients with QRS duration >120 to 150 ms, the ma-
jority of patients in the cohort actually had very wide QRS
complexes. There are no published data addressing the bene-
fit of CRT in patients with mildly prolonged QRS duration or
comparison with those with wide QRS duration.5,6,20 Lack of
reverse remodeling and clinical response after CRT have been
observed in some patients with wide QRS complexes,20,22
which is explained by the lack of significant systolic intraven-
tricular asynchrony before pacing.20 This observation may
be important by providing insight into more specific patient
selection for CRT.
The current data demonstrated that LV reverse remodel-
ing and clinical benefits were observed in patients with mildly
prolonged QRS complexes. However, the extent of these ben-
efits was less than in patients with wide QRS complexes
>150 ms. Half of the patients in group A were respon-
ders to reverse remodeling compared with two thirds in
group B. These responders had reduced LV volume, less
1062 Journal of Cardiovascular Electrophysiology Vol. 15, No. 9, September 2004

Figure 3. Regional myocardial velocity curves ob-

tained by tissue Doppler imaging at the basal septal
(yellow) and basal lateral (green) segments. A: In a
patient with left bundle branch block with QRS du-
ration of 180 ms, there was delay in peak systolic
contraction (arrows) of 95 ms in the lateral wall
compared to the septal wall. B: After biventricular
pacing, there was improvement in synchronicity as
reflected by the near overlapping of myocardial ve-
locity curves with a difference of only 20 ms. C: An-
other patient with mildly prolonged QRS duration
of 135 ms with intraventricular conduction delay.
There was delay in peak systolic conduction of 125
ms in the lateral wall compared to the septal wall
(arrow). D: After biventricular pacing, systolic syn-
chronicity was achieved as reflected by the perfect
overlapping of the myocardial velocity curves. In
both cases, there was significant left ventricular re-
verse remodeling with reduction of LV end-systolic
volume of 37% and 40%, respectively.
Yu et al. Efficacy of CRT for Mildly Prolonged QRS 1063

Figure 3. Continued
1064 Journal of Cardiovascular Electrophysiology Vol. 15, No. 9, September 2004
globular-shaped LV (favorable changes in sphericity index),
and improvement of systolic function. Importantly, improve-
ment of intraventricular mechanical asynchrony was demon-
strated only in the responders to reverse remodeling. This is
consistent with a strong correlation between the severity of
systolic asynchrony index and the degree of improvement of
LV volume and ejection fraction. That group A had a lower
overall systolic asynchrony index than group B likely ex-
plains the lower response rate in the former group. In fact, in
both groups, nearly all of the nonresponders had a low systolic
asynchrony index, whereas the majority of responders had
a high systolic asynchrony index. Furthermore, septolateral
wall asynchrony was severe before pacing in the responders
and was abolished after CRT. In contrast, this was not evident
in the nonresponders, supporting the fact that nonresponders
do not have significant systolic asynchrony; ECG showed
very wide QRS complexes in only 9 of 23 nonresponders.
The phenomenon of dissociation between electrical and me-
chanical asynchrony was demonstrated recently by tagging
magnetic resonance imaging, where synchronous mechani-
cal contraction could occur in the context of wide QRS du-
ration due to LV pacing.24 This echoes our observation that
an intrinsically prolonged QRS duration may not necessar-
ily be accompanied by mechanical asynchrony. Therefore,
the current data suggest that adjunct screening of mechanical
asynchrony may provide information helpful in the selec-
tion of potential responders to CRT, especially in those with
mildly prolonged QRS complexes in whom the response rate
is relatively lower due to the lower prevalence of mechani-
cal asynchrony. The potential usefulness of directly assessing
systolic asynchrony to predict reverse remodeling in patients
with wide QRS complexes has been suggested by a recent
study.22 This might be even more important for patients with
mildly prolonged QRS duration because the occurrence of
mechanical asynchrony is more variable and is less prevalent
than in patients with wide QRS complexes. Our recent study25
demonstrated that systolic asynchrony is not uncommon in
heart failure patients with normal QRS duration, based on
the same echocardiographic technique as used in the current
study.
Baseline QRS duration and change in QRS duration on
ECG had weak predictive power for reverse remodeling. They
were not independent predictors in a multivariate model.
Therefore, QRS duration is only a weak surrogate marker
of systolic asynchrony. The lack of association between QRS
duration and change in ejection fraction has been confirmed
by a study of 20 subjects.26 Assessment of systolic asyn-
chrony also has been performed by contrast echocardio-
graphy for regional variability27 or by counting the number
of segments with delayed long-axis contraction by TDI.23
These studies confirmed the correlation between assessment
of systolic asynchrony in predicting the gain in ejection frac-
tion after CRT.23,26,27 The delayed long-axis contraction, i.e.,
postsystolic shortening, typically occurs in early diastole af-
ter closure of the aortic valve.23 Theoretically, this component
of movement makes no contribution to the systolic function
of the heart and on its own does not measure systolic asyn-
chrony.28 However, it may serve as another surrogate marker
of systolic asynchrony because it could reflect the presence
of viable myocardium that developed delayed and uncoordi-
nated contraction during cardiac disease such as myocardial
ischemia.28 Our current method of using the systolic asyn-
chrony index by TDI not only examines the relationship be-
tween systolic synchronicity and volumetric response, it also
derives a useful cutoff value for selection of potential respon-
ders to CRT, with acceptably high sensitivity and specificity.
Further studies are needed to determine which parameter(s)
is the most useful for predicting a response to CRT.
Improvement of symptoms, exercise capacity, and quality
of life was observed after CRT in both QRS groups. Similar
to the degree of reverse remodeling and intraventricular asyn-
chrony, most of these parameters were improved to a greater
extent in group B than in group A. Therefore, in group B
patients in whom there is more severe systolic asynchrony,
correction of the asynchrony will parallel the improvement
of clinical status. Recently completed or ongoing large multi-
center trials, such as the COMPANION and CARE-HF,29,30
are investigating the benefit of CRT in patients with QRS
>120 ms and will provide further insight into the role of
CRT in patients with mildly prolonged QRS complexes.
References
1. Daubert JC, Ritter P, Le Breton H, Gras D, Leclercq C, Lazarus A,
Mugica J, Mabo P, Cazeau S: Permanent left ventricular pacing with
transvenous leads inserted into the coronary veins. Pacing Clin Electro-
physiol 1998;21:239-245.
2. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C,
Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C,
Daubert JC: Effects of multisite biventricular pacing in patients with
heart failure and intraventricular conduction delay. N Engl J Med
2001;344:873-880.
3. Abraham WT, Fisher WG, Smith AL, DeLurgio DB, Leon AR, Loh
E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp
RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J:
Cardiac resynchronization in chronic heart failure. N Engl J Med
2002;346:1845-1853.
4. Gras D, Leclercq C, Tang AS, Bucknall C, Luttikhuis HO, Kirstein-
Pedersen A: Cardiac resynchronization therapy in advanced heart
failure-the multicenter InSync clinical study. Eur J Heart Fail
2002;4:311-320.
5. Yu CM, Chau E, Sanderson JE, Fan K, Tang MO, Fung WH, Lin H,
Kong SL, Lam YM, Hill MR, Lau CP: Tissue Doppler echocardio-
graphic evidence of reverse remodeling and improved synchronicity by
simultaneously delaying regional contraction after biventricular pacing
therapy in heart failure. Circulation 2002;105:438-445.
6. Saxon LA, De Marco T, Schafer J, Chatterjee K, Kumar UN, Fos-
ter E: Effects of long- term biventricular stimulation for resynchro-
nization on echocardiographic measures of remodeling. Circulation
2002;105:1304-1310.
7. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P,
Mortensen P, Klein H: The Pacing Therapies for Congestive Heart
Failure (PATH-CHF) study: Rationale, design, and endpoints of a
prospective randomized multicenter study. Am J Cardiol 1999;83:130D-
135D.
8. Nelson GS, Curry CW, Wyman BT, Kramer A, Declerck J, Talbot M,
Douglas MR, Berger RD, McVeigh ER, Kass DA: Predictors of sys-
tolic augmentation from left ventricular preexcitation in patients with
dilated cardiomyopathy and intraventricular conduction delay. Circula-
tion 2000;101:2703-2709.
9. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky
MA, Kerber RE, Naccarelli GV, Schoenfeld MH, Silka MJ, Winters SL,
Gibbons RJ, Antman EM, Alpert JS, Gregoratos G, Hiratzka LF, Faxon
DP, Jacobs AK, Fuster V, Smith SC Jr: ACC/AHA/NASPE 2002 guide-
line update for implantation of cardiac pacemakers and antiarrhythmia
devices: Summary article: A report of the American College of Cardi-
ology/American Heart Association Task Force on Practice Guidelines
(ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guide-
lines). Circulation 2002;106:2145-2161.
10. Lau CP, Yu CM, Chau E, Fan K, Tse HF, Lee K, Tang MO, Wan
SH, Law TC, Lee PY, Lam YM, Hill MR: Reversal of left ventricular
remodeling by synchronous biventricular pacing in heart failure. Pacing
Clin Electrophysiol 2000;23:1722-1725.
11. Kindermann M, Frohlig G, Doerr T, Schieffer H: Optimizing the AV
delay in DDD pacemaker patients with high degree AV block: Mitral

valve Doppler versus impedance cardiography. Pacing Clin Electro-
physiol 1997;20:2453-2462.
12. Bargiggia GS, Bertucci C, Recusani F, Raisaro A, de Servi S, Valdes-
Cruz LM, Sahn DJ, Tronconi L: A new method for estimating left ven-
tricular dP/dt by continuous wave Doppler-echocardiography. Valida-
tion studies at cardiac catheterization. Circulation 1989;80:1287-1292.
13. Pai RG, Gill KS: Amplitudes, durations, and timings of apically di-
rected left ventricular myocardial velocities: I. Their normal pattern
and coupling to ventricular filling and ejection. J Am Soc Echocardiogr
1998;11:105-111.
14. Miyatake K, Yamagishi M, Tanaka N, Uematsu M, Yamazaki N, Mine
Y, Sano A, Hirama M: New method for evaluating left ventricular wall
motion by color-coded tissue Doppler imaging: In vitro and in vivo
studies. J Am Coll Cardiol 1995;25:717-724.
15. Yu CM, Wang Q, Lau CP, Tse HF, Leung SK, Lee KL, Tsang V, Ayers
G: Reversible impairment of left and right ventricular systolic and dias-
tolic function during short-lasting atrial fibrillation in patients with an
implantable atrial defibrillator: A tissue Doppler imaging study. Pacing
Clin Electrophysiol 2001;24:979-988.
16. Yu CM, Lin H, Yang H, Kong SL, Zhang Q, Lee SWL: Progression of
systolic abnormalities in patients with isolated diastolic heart failure
and diastolic dysfunction. Circulation 2002;105:1195-1201.
17. Fleming AD, McDicken WN, Sutherland GR, Hoskins PR: Assessment
of colour Doppler tissue imaging using test-phantoms. Ultrasound Med
Biol 1994;20:937-951.
18. Naito J, Masuyama T, Mano T, Yamamoto K, Doi Y, Kondo H, Hori M,
Shiba A, Murakami K, Shimura T: Validation of transthoracic myocar-
dial ultrasonic tissue characterization: Comparison of transthoracic and
open-chest measurements of integrated backscatter. Ultrasound Med
Biol 1995;21:33-40.
19. Rodriguez L, Garcia M, Ares M, Griffin BP, Nakatani S, Thomas JD:
Assessment of mitral annular dynamics during diastole by Doppler tis-
sue imaging: Comparison with mitral Doppler inflow in subjects without
heart disease and in patients with left ventricular hypertrophy. Am Heart
J 1996;131:982-987.
20. Stellbrink C, Breithardt OA, Franke A, Sack S, Bakker P, Auricchio A,
Pochet T, Salo R, Kramer A, Spinelli J: Impact of cardiac resynchroniza-
tion therapy using hemodynamically optimized pacing on left ventricu-
lar remodeling in patients with congestive heart failure and ventricular
conduction disturbances. J Am Coll Cardiol 2001;38:1957-1965.
21. Pitzalis MV, Iacoviello M, Romito R, Massari F, Rizzon B, Luzzi G,
Yu et al. Efficacy of CRT for Mildly Prolonged QRS 1065
Guida P, Andriani A, Mastropasqua F, Rizzon P: Cardiac resynchro-
nization therapy tailored by echocardiographic evaluation of ventricular
asynchrony. J Am Coll Cardiol 2002;40:1615-1622.
22. Yu CM, Fung WH, Lin H, Zhang Q, Sanderson JE, Lau CP: Predictors
of left ventricular reverse remodeling after cardiac resynchronization
therapy for heart failure secondary to idiopathic dilated or ischemic
cardiomyopathy. Am J Cardiol 2003;91:684-688.
23. Sogaard P, Egeblad H, Kim WY, Jensen HK, Pedersen AK, Kristensen
BO, Mortensen PT: Tissue Doppler imaging predicts improved systolic
performance and reversed left ventricular remodeling during long-term
cardiac resynchronization therapy. J Am Coll Cardiol 2002;40:723-730.
24. Leclercq C, Faris O, Tunin R, Johnson J, Kato R, Evans F, Spinelli J,
Halperin H, McVeigh E, Kass DA: Systolic improvement and mechani-
cal resynchronization does not require electrical synchrony in the dilated
failing heart with left bundle-branch block. Circulation 2002;106:1760-
1763.
25. Yu CM, Lin H, Zhang Q, Sanderson JE: High prevalence of left ventric-
ular systolic and diastolic asynchrony in patients with congestive heart
failure and normal QRS duration. Heart 2003;89:54-60.
26. Sogaard P, Kim WY, Jensen HK, Mortensen P, Pedersen AK, Kristensen
B, Egeblad H: Impact of acute biventricular pacing on left ventricular
performance and volumes in patients with severe heart failure: A tissue
Doppler and three-dimensional echocardiographic study. Cardiology
2001;95:173-182.
27 Kawaguchi M, Murabayashi T, Fetics BJ, Nelson GS, Samejima H,
Nevo E, Kass DA: Quantitation of basal dyssynchrony and acute resyn-
chronization from left or biventricular pacing by novel echo-contrast
variability imaging. J Am Coll Cardiol 2002;39:2052-2058.
28. Skulstad H, Edvardsen T, Urheim S, Rabben SI, Stugaard M,
Lyseggen E, Ihlen H, Smiseth OA: Postsystolic shortening in is-
chemic myocardium: active contraction or passive recoil? Circulation
2002;106:718-724.
29. Bristow MR, Feldman AM, Saxon LA: Heart failure management using
implantable devices for ventricular resynchronization: Comparison of
Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure
(COMPANION) trial. COMPANION Steering Committee and COM-
PANION Clinical Investigators. J Card Fail 2000;6:276-285.
30. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D,
Kappenberger L, Klein W, Tavazzi L: The CARE-HF study (CArdiac
REsynchronisation in Heart Failure study): Rationale, design and end-
points. Eur J Heart Fail 2001;3:481-489.