Effect of Cardiac Resynchronization Therapy on
Inducibility of Ventricular Tachyarrhythmias in Cardiac
Arrest Survivors With Either Ischemic or Idiopathic
Dilated Cardiomyopathy
Philippine Kis, MD, Jeroen J. Bax, MD, PhD, Sander G. Molhoek, MD,
Gabe B. Bleeker, MD, Katja Zeppenfeld, MD, PhD, Marianne Bootsma, MD, PhD,
Lieselot van Erven, MD, PhD, Paul Steendijk, PhD, Ernst E. van der Wall, MD, PhD,
and Martin J. Schalij, MD, PhD
We evaluated whether long-term cardiac resynchro-
nization therapy affects the inducibility of ventricular
tachyarrhythmias in relation to reverse remodeling in
cardiac arrest survivors with either ischemic or idio-
pathic dilated cardiomyopathy. Clinical, electrophysi-
ologic, and echocardiographic data of 18 patients
were obtained before and after 6 months of cardiac
resynchronization. 2005 by Excerpta Medica Inc.
(Am J Cardiol 2005;95:11111114)
A growing number of randomized clinical trials has
established the beneficial effects of cardiac re-
synchronization therapy (CRT) on symptoms, exer-
cise capacity, left ventricular (LV) systolic perfor-
mance, and LV reverse remodeling.13 In addition,
several reports have suggested that CRT may also
reduce the frequency of ventricular ectopy and appro-
priate implantable cardioverter-defibrillator (ICD)
therapy.4 7 Preliminary data have also shown a reduc-
tion in the prevalence of ventricular tachyarrhythmic
episodes in patients treated with CRT.8 The reduction
in ventricular arrhythmias was related to reverse re-
modeling after CRT, suggesting that reduced wall
tension may lead to a reduction in ventricular arrhyth-
mias. To further substantiate this hypothesis, we eval-
uated the inducibility of ventricular tachyarrhythmias
during an electrophysiologic study after 6 months of
CRT in cardiac arrest survivors treated with a com-
bined CRT-ICD device and its relation to reverse
remodeling as a result of CRT.
with 10 ms until refractoriness or the shortest coupling
Nineteen consecutive sudden cardiac arrest survi-
vors with advanced heart failure who were implanted
with a CRT-ICD device were evaluated. Implantation
of an ICD in these patients was based on standard
therapy guidelines.9 Eligibility for CRT was based on
the following criteria: (1) advanced heart failure with
New York Heart Association functional class III or
IV, (2) LV ejection fraction 35%, and (3) wide QRS
From the Department of Cardiology, Leiden University Medical Center,
Leiden, The Netherlands. Drs. Molhoek and Bleeker were supported by
Grants 2001D015 and 2002B109, respectively, from the Dutch Heart
Foundation, The Hague, The Netherlands. Dr. Baxs address is: Depart-
ment of Cardiology, Leiden University Medical Center, Albinusdreef 2,
2333 ZA Leiden, The Netherlands. E-mail: jbax@knoware.
nl. Manuscript received November 8, 2004; revised manuscript
received and accepted December 30, 2004.
2005 by Excerpta Medica Inc. All rights reserved.
The American Journal of Cardiology Vol. 95 May 1, 2005
complex (120 ms) with a left bundle branch block
pattern on the electrocardiogram. Patients with isch-
emic or nonischemic cardiomyopathy were evaluated.
Patients with atrial fibrillation were not excluded. Six
months after a baseline electrophysiologic study and
the implantation of a CRT-ICD device, the inducibil-
ity of ventricular tachycardia/ventricular fibrillation
(VT/VF) was evaluated as part of standard clinical
practice.
First, a coronary sinus venogram was obtained
using the balloon catheter. Next, the LV pacing lead
(Easytrack 4512 to 80, Guidant, Minneapolis, Minne-
sota, or Attain-SD model 4189, Medtronic Inc., St.
Paul, Minnesota) was inserted transvenously via the
subclavian route with the help of an 8Fr guiding
catheter, and positioned in a posterolateral vein.10 The
right atrial and 2 ventricular leads were positioned
conventionally. All leads were connected to a dual-
chamber biventricular ICD (Contak CD or Contak
Renewal, Guidant, or InSync CD, Medtronic Inc.).
Three quadripolar catheters were inserted trans-
venously and positioned in the high right atrium, at the
His bundle, and in the right ventricular (RV) apex.
Pacing was performed at twice the pacing threshold.
To induce VT/VF, programmed electrical stimulation
was performed from the RV apex and subsequently
from the RV outflow tract according to a standardized
protocol, applying up to 3 extrastimuli after 8-beat
drive trains at 3 different basic cycle lengths (600,
500, and 400 ms). The extrastimuli were decremented
interval (200 ms) was reached. Inducibility of VT/VF
was defined as the induction of sustained VT (30
seconds) and/or VF.
At 6 months, a second electrophysiologic study
was performed according to the same protocol but
through the ICD (via the RV lead). Consequently,
stimulation through the RV outflow tract could not be
performed. To compare the results of both electro-
physiologic studies, we only considered the results of
stimulation from the RV apex of the first electrophysi-
ologic study. Accordingly, 1 patient who had only
been inducible with stimulation in the RV outflow
tract during the first study was excluded.
Patients were imaged in the left lateral decubitus
position using a commercially available system
(Vingmed system FiVe/Vivid 7, General Electric-
0002-9149/05/$see front matter 1111
doi:10.1016/j.amjcard.2005.01.029
Vingmed, Milwaukee, Wisconsin). Images were ob-
tained using a 3.5-MHz transducer at a depth of 16 cm
in the parasternal and apical views (standard long-axis
and 2- and 4-chamber images). Standard 2-dimen-
sional and color Doppler data, triggered to the QRS
complex, were saved in cineloop format. LV ejection
fraction and LV volumes were derived from the con-
ventional apical 2- and 4-chamber images using the
biplane Simpsons rule.11 The severity of mitral re-
gurgitation was graded semiquantitatively from color
flow Doppler in the conventional parasternal long-axis
and apical 4-chamber images. Mitral regurgitation
was characterized as mild 1 (jet area/left atrial
area 10%), moderate 2 (jet area/left atrial area
10% to 20%), moderately severe 3 (jet area/left
atrial area 20% to 45%), and severe 4 (jet area/left
atrial area 45%).12 All data (baseline, follow-up)
were obtained by 2 independent observers blinded to
all other data.
Patients were evaluated clinically at baseline and
after 6 months of CRT. Heart failure symptoms were
classified according to the New York Heart Associa-
tion score. Quality-of-life score was assessed using
the Minnesota Living with Heart Failure question-
naire.13 Exercise capacity was evaluated using the
6-minute hall walk test.14 A surface electrocardiogram
was obtained (12 leads at a study speed of 50 mm/s) to
establish QRS morphology and duration before and
after 6 months of CRT.
Data are expressed as mean SD. Comparison of FIGURE 1. Clinical evaluation before (left bars) and after (right
data was performed using the Students t test for bars) 6 months of CRT . (A) New York Heart Association (NYHA)
paired and unpaired data when appropriate, whereas classification, (B) quality-of-life (QOL) score, and (C) the 6-minute
the Wilcoxon signed rank test was performed in case hall walk test (6-MWT).
of markedly skewed distribution of the data. McNemars
test for paired dichotomous data was performed to
compare inducibility before and after 6 months of Association class decreased from 3.0 0 to 2.1 0.8
CRT. For all tests, a p value 0.05 was considered (p 0.01). The quality-of-life score decreased from
significant. Patients who were part of this study were 41 12 to 24 13 (p 0.01). In addition, exercise
not included in other published studies. capacity improved, reflected by a significant improve-
We analyzed 18 patients (15 men and 3 women) ment in the 6-minute hall walk test from 321 73 to
after the exclusion of 1 patient. The mean age of the 444 136 m (p 0.01) after 6 months of CRT
study group at the time of implantation of the CRT- (Figure 1).
ICD device was 62 11 years (range 38 to 81). Results of the first electrophysiologic study are
Etiology of underlying heart failure was ischemic displayed in Table 1. In 15 of 18 patients (83%), a
cardiomyopathy in 10 patients and idiopathic dilated sustained VT was inducible. Three patients had no
cardiomyopathy in 8 patients. All patients had been inducible VT/VF. After an average of 7.1 0.8
referred with aborted sudden death, 6 deaths due to months of CRT, the second electrophysiologic study
VF and 12 due to a fast sustained VT (average cycle was performed (Table 1). As opposed to the first
length of VT, 244 22 ms) with hemodynamic study, a sustained VT was inducible in only 6 patients
collapse. All patients received optimized (if tolerated) (33%, p 0.01). Thus, in 9 of 15 patients (60%),
medical therapy, including diuretics and oral antico- ventricular arrhythmias were no longer inducible at
agulants in all, angiotensin-converting enzyme inhib- the second study. Of note, no patient experienced
itors in 83%, blockers in 66%, and spironolactone in increased inducibility; the 3 patients in whom induc-
50% of patients. In addition, amiodarone was admin- ibility could not be achieved remained noninducible
istered to 13 patients (72%) and sotalol to 4 patients during the second electrophysiologic study. Hemody-
(22%). Medication remained unchanged during the namics (heart rate and blood pressure) were compa-
study. rable during both electrophysiologic studies. This was
At baseline, all patients were in New York Heart also the case during both echocardiograhic exami-
Association class III (n 18), with an average QRS nations.
duration of 185 29 ms. The electrocardiogram LV ejection fraction at baseline was 19 5%. All
showed a left bundle branch block pattern in all 18 patients had severely dilated left ventricles as evi-
patients. After 6 months of CRT, the New York Heart denced by LV end-diastolic and end-systolic volumes

1112 THE AMERICAN JOURNAL OF CARDIOLOGY VOL. 95 MAY 1, 2005

 TABLE 1 Results of Electrophysiologic Studies Both Before (study 1) and After (study 2) Six Months of Resynchronization Therapy
Indication Underlying Inducibility Inducibility Decreased
Patient No. (EP study) Cardiomyopathy (EP study 1) S1,S1 (ms) Extras (EP study 2) S1,S1 (ms) Extras Inducibility

1 VT Ischemic Yes 500 2 No Yes

2 VT Dilated Yes 400 2 Yes 600 3 No
3 VF Dilated No No No
4 VT Ischemic Yes 400 2 Yes 500 2 No
5 VT Dilated Yes 400 2 No Yes
6 VT Ischemic Yes 400 3 No Yes
7 VF Dilated No No No
8 VT Dilated Yes 500 3 Yes 400 1 No
9 VT Ischemic Yes 500 3 Yes 500 2 No
10 VF Ischemic Yes 600 2 No Yes
11 VF Dilated Yes 600 3 No Yes
12 VT Dilated Yes 500 3 No Yes
13 VT Ischemic Yes 400 2 No Yes
14 VT Dilated Yes 500 3 No Yes
15 VT Ischemic Yes 600 3 Yes 500 3 No
16 VT Ischemic Yes 500 3 Yes 500 2 No
17 VF Ischemic Yes 400 3 No Yes
18 VF Ischemic No No No
No. of inducible 15 6 9*
patients:

*The number of patients with inducible ventricular tachyarrhythmias decreased significantly (p 0.01).
EP electrophysiologic.

duction in LV end-diastolic volume,

TABLE 2 Echocardiographic Results Both Before and After Six Months of Cardiac
Resynchronization Therapy from 293 67 to 258 69 ml (p
0.01), whereas LV end-diastolic
Before CRT 6-mo Follow-up p Value volumes in patients with continuing
Loss of inducibility (n 9) inducibility did not change (from
LV ejection fraction (%) 17 5 24 8 0.01 258 30 to 252 41 ml, p NS).
LV end-diastolic volume (ml) 293 67 258 69 0.01 Similar results were observed for
LV end-systolic volume (ml) 244 69 198 69 0.01
Continuing inducibility (n 6) end-systolic volumes. In patients
LV ejection fraction (%) 19 2 21 4 NS with loss of inducibility, LV end-
LV end-diastolic volume (ml) 258 30 252 41 NS systolic volumes were decreased
LV end-systolic volume (ml) 208 27 199 35 NS from 244 69 to 198 69 ml (p
0.01). Patients who remained in-
ducible had almost similar end-sys-
of 274 61 and 224 62 ml, respectively. After 6 tolic volumes before and after 6 months of CRT (208
months of CRT, reverse remodeling was observed. 27 and 199 35 ml, p NS).
End-diastolic volume decreased to 254 69 ml (p St. John Sutton et al15 recently demonstrated that
0.05) and end-systolic volume decreased to 198 ongoing LV remodeling resulted in a higher incidence
66 ml (p 0.01). However, close examination of the of ventricular arrhythmias due to increased LV wall
data demonstrated that this decrease in volumes is stress and its consequences on LV structure and com-
solely attributable to the patient group that had loss of position. As a result, anisotropic reentry, an important
inducibility during the second electrophysiologic mechanism underlying ventricular arrhythmias, may
study (Table 2). In addition, before CRT, 4 patients be facilitated because this originates from areas of
had severe (grade 3), 10 patients had moderate slowed impulse propagation and unidirectional con-
(grade 2), and 4 patients had mild (grade 1) mitral duction block.16 This process may be amplified by
regurgitation. After 6 months of CRT, in 9 patients elevated plasma levels of adrenergic neurohormones
(50%), the degree of mitral regurgitation had im- in patients with end-stage heart failure.17,18 Con-
proved by 1 grade. versely, reverse remodeling, as observed after pro-
longed CRT, may reduce wall stress and invert this
The main finding of our study was that the induc- process.19 In addition, CRT may lead to decreased
ibility of VT/VF was decreased in patients with sig- plasma-norepinephrine levels.20 Reduction in wall
nificant LV reverse remodeling after 6 months of stress may therefore be explanatory for the decreased
treatment with a CRT-ICD device. prevalence of ventricular arrhythmias, such as we
We observed a striking difference between patients recently demonstrated in 18 patients after 12 months
with loss of inducibility and patients who remained of CRT.8 The loss of inducibility of ventricular tachy-
inducible in terms of LV remodeling. Patients with arrhythmias observed in this study may also be ex-
loss of inducibility during CRT had a significant re- plained by reduced wall stress.

BRIEF REPORTS 1113

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Long-Term Effects of Carvedilol or Metoprolol on
Left Ventricular Function in Ischemic and
Nonischemic Cardiomyopathy
Philip Green, MS, Michael Anshelevich, MD, Ashok Talreja, MD, Joyce L. Burcham,
Srinivas M. Ravi, MD, Jamshid Shirani, MD, and Thierry H. Le Jemtel, MD
Data regarding the effects of blockers on left ven-
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ischemic and nonischemic cardiomyopathy. Echocar-
diograms of 72 patients with ischemic and nonisch-
emic cardiomyopathy, who were free of clinical
events susceptible to alter LV function while receiving
carvedilol or metoprolol for at least 24 months, were
prospectively reanalyzed. Twelve months after
-blocker initiation, LV ejection fraction (EF) increased
by >5% in 75% of patients, whereas EF failed to
increase by 5% or decreased in the remaining 25%.
Over the subsequent 32 months, LVEF increased fur-
ther in patients who had experienced an initial EF
increase by >5%, whereas EF tended to further de-
From the Department of Medicine, Albert Einstein College of Medi-
cine, Bronx; and Our Lady of Mercy Medical Center, Bronx, New
York. Dr. Le Jemtels address is: Albert Einstein College of Medicine,
Room G-46, Forchheimer Building, 1300 Morris Park Avenue, Bronx,
New York 10461. E-mail: lejemtel@aecom.yu.edu. Manuscript re-
ceived September 14, 2004; revised manuscript received and ac-
cepted January 4, 2005.
1114 2005 by Excerpta Medica Inc. All rights reserved.
The American Journal of Cardiology Vol. 95 May 1, 2005
NASPE Committee to Update the 1998 Pacemaker Guidelines). J Cardiovasc
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Failure questionnaire as a measure of therapeutic response to enalapril or placebo.
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for assessing exercise capacity in chronic heart failure. BMJ 1986;292:653 655.
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E, Pfeffer MA. Left ventricular remodeling and ventricular arrhythmias after
myocardial infarction. Circulation 2003;107:25772582.
16. de Bakker JM, van Capelle FJ, Janse MJ, Wilde AA, Coronel R, Becker AE,
Dingemans KP, van Hemel NM, Hauer RN. Reentry as a cause of ventricular
tachycardia in patients with chronic ischemic heart disease: electrophysiologic
and anatomic correlation. Circulation 1988;77:589 606.
17. Kjaer A, Hesse B. Heart failure and neuroendocrine activation: diagnostic,
prognostic and therapeutic perspectives. Clin Physiol 2001;21:661 672.
18. Aronson D, Burger AJ. Neurohumoral activation and ventricular arrhythmias
in patients with decompensated congestive heart failure: role of endothelin.
Pacing Clin Electrophysiol 2003;26:703710.
19. Nguyen T, El Salibi E, Rouleau JL. Postinfarction survival and inducibility of
ventricular arrhythmias in the spontaneously hypertensive rat: effects of ramipril
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20. Hamdan MH, Zagrodzky JD, Joglar JA, Sheehan CJ, Ramaswamy K, Erdner
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tion. Circulation 2000;102:10271032.
PhD,
crease in patients who had experienced an initial EF
increase of <5% or a decrease. Thus, the benefits of
carvedilol or metoprolol on LV function are long last-
ing in patients with ischemic or nonischemic cardio-
myopathy who are free of events susceptible to alter
LV function while receiving blockade. 2005 by
Excerpta Medica Inc.
(Am J Cardiol 2005;95:1114 1116)
T he present study was undertaken to prospectively
reanalyze serial 2-dimensional echocardiograms
collected from patients with ischemic and nonisch-
emic cardiomyopathy who received -blocker therapy
for 24 months and did not experience events that
could have interfered with the effect of blockade on
left ventricular (LV) function.
Among the 648 patients with congestive heart fail-
ure followed at the Montefiore Medical Center heart
failure service, 72 were eligible for the study based on
the following criteria: (1) they had received -blocker
therapy for 24 months; (2) they had undergone high-
0002-9149/05/$see front matter
doi:10.1016/j.amjcard.2005.01.030