Download Print - Circulation

29
Efficacy of Antiarrhythmic Drugs in Patients
With Arrhythmogenic Right Ventricular Disease
Results in Patients With Inducible and Noninducible
Ventricular Tachycardia
Thomas Wichter, MD; Martin Borggrefe, MD; Wilhelm Haverkamp, MD;
Xu Chen, MD; and Gunter Breithardt, MD, FESC, FACC
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Background. Ventricular tachyarrhythmias are the major clinical manifestation of arrhythmogenic
right ventricular disease. Although antiarrhythmic therapy has been widely advocated, there is only
limited information available on the efficacy of antiarrhythmic drugs in these patients.
Methods and Results. The short- and long-term efficacies of various antiarrhythmic agents were
retrospectively and prospectively analyzed in 81 patients (mean age, 39+14 years; range, 16-68 years;
61.7% males) with arrhythmogenic right ventricular disease. In 42 patients with inducible ventricular
tachycardia during programmed ventricular stimulation, the following efficacy rates were obtained: class
Ia and lb drugs (n=18), 5.6%; class Ic drugs (n=25), 12%; 1-blockers (n=8), 0%o; sotalol (n=38), 68.4%;
amiodarone (n=13), 15.4%; verapamil (n=5), 0%o; and drug combinations (n=26), 15.4%. Only one of the
10 patients not responding to sotalol was treated effectively by amiodarone, whereas the remaining nine
patients proved to be drug refractory toward all other drugs tested (3.8±2.3 drugs, including amiodarone
in five cases) and underwent nonpharmacological therapy. During a follow-up of 34±25 months, three of
the 31 patients (9.7%) discharged on pharmacological therapy had nonfatal recurrences of ventricular
tachycardia after 0.5, 51, and 63 months, respectively. In 39 patients with noninducible ventricular
tachycardia during programmed ventricular stimulation, the following efficacy rates were observed: class
Ia and Ib drugs (n=16), 0%1; class Ic agents (n=23), 17.4%; 13-blockers (n=7), 28.6%; sotalol (n=35),
82.8%; amiodarone (n=4), 25%; verapamil (n=24), 50%1; and drug combinations (n=11), 9.1%. During a
follow-up of 14±+13 months, four of 33 patients (12.1%) discharged on antiarrhythmic drugs had nonfatal
relapses of their clinical ventricular arrhythmia.
Conclusions. Thus, in arrhythmogenic right ventricular disease, sotalol proved to be highly effective in
patients with inducible as well as noninducible ventricular tachycardia. Patients with inducible ventricular tachycardia not responding to sotalol are likely to not respond to other antiarrhythmic drugs and
should be considered for nonpharmacological therapy without further drug testing. Amiodarone did not
prove to be more effective than sotalol and may not be an alternative because of frequent side effects
during long-term therapy, especially in young patients. Verapamil and 1-blockers were effective in a
considerable number of patients with noninducible ventricular tachycardia and may be a therapeutic
alternative in this subgroup. Class I agents appear to be rarely effective in the treatment of both inducible
and noninducible ventricular tachycardia in arrhythmogenic right ventricular disease. (Circulation
1992;86:29-37)
KEY WoRDs * right ventricle * dysplasia, right ventricular * antiarrhythmics * ventricular
tachycardia
rrhythmogenic right ventricular disease (ARVD)
is a rare myocardial disorder characterized by
ventricular tachyarrhythmias originating from
the right ventricle, frequent repolarization abnormalities in the right precordial leads of the surface ECG,
and localized or diffuse right ventricular contraction
abnormalities detectable by two-dimensional echocardiography, gated nuclear scintigraphy, or right ventricular
A
From the Hospital of the Westfalische Wilhelms-University,
Department of Cardiology and Angiology, Munster, Germany.
Address for correspondence: Thomas Wichter, MD, Medizinische Klinik und Poliklinik, Innere Medizin C (Kardiologie und
Angiologie), Westfalische Wilhelms-Universitat Munster, AlbertSchweitzer Strasse 33, D-4400 MIunster, Germany.
Received August 26, 1991; revision accepted March 13, 1992.
angiography.1-5 The underlying structural cardiac abnormalities may be examined by endomyocardial biopsy
or, more recently, magnetic resonance imaging.6-'1
Patients with arrhythmogenic right ventricular disease and inducible ventricular tachycardia normally
present with spontaneous sustained monomorphic ventricular tachycardia. They frequently exhibit more extensive global or regional right ventricular contraction
abnormalities detectable by various imaging techniques.
In contrast, patients with noninducible ventricular
tachycardia normally present with frequent ventricular
runs or repetitive nonsustained ventricular tachycardia
and only circumscribed contraction abnormalities of the
right ventricle,12-"5 mostly not reducing global right
ventricular ejection fraction.
30
Circulation Vol 86, No 1 July 1992
TABLE 1. Clinical Characteristics of Study Patients
VT inducible
VT noninducible
(n=42)
(n=39)
p
<0.001
85.7
35.9
Male (%)
NS
34±13.5
34±14.1
Age at onset of symptoms (mean+SD, years)
40±13.3
NS
38±14.5
Age at diagnosis (mean±SD, years)
<0.0001
20.5
92.9
Presenting arrhythmia: sustained VT (%)
<0.0001
79.5
7.1
Presenting arrhythmia: nonsustained VT (%)
NS
3.9±2.8
4.3±3.5
Antiarrhythmic drugs tested (mean±SD)
NS
64.7
43.3
(n=34)
(n=30)
Abnormal fibrolipomatosis (%)
<0.0001
56±6.1
45±8.3
RV-EF (mean±SD, %)
NS
70±11.2
74±8.7
LV-EF (mean+SD, %)
VT, ventricular tachycardia; RV-EF, right ventricular ejection fraction; LV-EF, left ventricular ejection fraction.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Antiarrhythmic drug therapy frequently is considered
to be indicated in patients with arrhythmogenic right
ventricular disease to prevent serious arrhythmic symptoms or complications including sudden cardiac death,
which has been reported in both subgroups.'6,17 Although various authors have reported on successful
antiarrhythmic therapy with various drugs and drug
combinations in small numbers of patients, pharmacological treatment still is empiric.14"15"18-23 Recommendations concerning the most effective drugs and dosages
have not been established. Therefore, we analyzed
retrospectively and prospectively the short- and longterm efficacies of different antiarrhythmic drugs in 81
patients with arrhythmogenic right ventricular disease
and inducible or noninducible ventricular tachycardia
during programmed ventricular stimulation.
Methods
Study Patients
The study population comprised 81 patients (50 males
and 31 females) ranging in age from 16 to 68 years
(mean, 39±13.9 years) with proven or highly suspected
arrhythmogenic right ventricular disease on the basis of
the 12-lead surface ECG during sinus rhythm and
documented sustained or nonsustained ventricular
tachycardia (n=81), noninvasive imaging techniques
such as two-dimensional echocardiography (n=81) and
magnetic resonance imaging (n=50), right and left
ventricular angiography and coronary angiography
(n=81), and endomyocardial biopsy (n=64). The first
patient included in this study was diagnosed in 1977.
The baseline characteristics of the patients are summarized in Table 1.
Diagnosis ofArrhythmogenic Right
Ventricular Disease
Arrhythmogenic right ventricular disease was diagnosed in the presence of documented sustained or
nonsustained ventricular tachycardia of left bundle
branch block morphology, repolarization abnormalities
in the right precordial leads of the surface ECG in sinus
rhythm, and evidence of characteristic right ventricular
contraction abnormalities. Coronary artery disease, dilative or hypertrophic cardiomyopathy, and congenital
or acquired valvular heart disease were excluded. The
more specific diagnosis of arrhythmogenic right ventricular dysplasia was made in the presence of the abovementioned criteria and the additional evidence of ab-
normal fibrolipomatous infiltration of the right
ventricular myocardium,34 which was detected by endomyocardial biopsy in 35 of 64 patients (54.7%). Patients
with idiopathic ventricular tachycardia that was diagnosed after exclusion of morphological, functional, and
structural heart disease3 were not included in this study.
Characteristic angiographic findings suggestive of arrhythmogenic right ventricular disease were localized
akinesia, dyskinesia, aneurysms, bulgings, or outpouchings,24-27 which may also be detectable by two-dimensional echocardiography.28-32 In addition, nonspecific
angiographic findings like horizontal fissures and slow
dye evacuation frequently were observed. Angiographic
global ejection fractions were determined uniplane for
the left ventricle by calculation according to the arealength method and biplane for the right ventricle according to Boak's formula.33 Endomyocardial biopsies
were taken from different right ventricular areas
(3.4±1.6 samples per patient; range, one to eight) by
preference of regions of documented contraction
abnormalities.
Electrophysiological Study
All patients underwent an invasive electrophysiological study with programmed ventricular stimulation off
antiarrhythmic drugs in the nonsedated state after
written informed consent was obtained. Single and
double extrastimuli were delivered at two right ventricular stimulation sites (apex and outflow tract) at twicediastolic threshold during sinus rhythm and basic drive
cycle lengths of 500, 430, 370, and 330 msec.34 If no
sustained ventricular tachyarrhythmia was inducible, a
third extrastimulus was introduced during 500-msec
drive cycle length. If still no ventricular tachycardia was
inducible, the entire sequence was repeated after intravenous isoprenaline infusion titrated to achieve an
increase of basic heart rate by 25% or more.
Definitions
Spontaneous and induced ventricular tachyarrhythmias were classified according to the definitions listed in
Table 2.
Criteria of Drug Efficacy
Various antiarrhythmic drugs of different classes of
action according to the classification of Vaughan-Williams35 were used in both patient groups. The drugs and
Wichter et al Antiarrhythmic Drug Efficacy in ARVD
TABLE 2. Definitions
3-10 consecutive ventricular beats
Ventricular run
Nonsustained VT
>10 consecutive ventricular beats, <30
seconds' duration
Sustained VT
>30 seconds' duration or prior termination
because of hemodynamic deterioration
Inducible VT
Sustained VT inducible by PVS at baseline
or after isoprenaline infusion
No sustained VT inducible by PVS
including isoprenaline infusion
VT, ventricular tachycardia; PVS, programmed ventricular
stimulation.
Noninducible VT
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
corresponding mean daily dosages are listed in Tables 3
and 4.
In the retrospective part of data analysis, information
on all previously administered drugs were extracted
from the records of the referring physicians and hospitals and by interviewing the patients. Clinical drug
failure was defined as recurrence of ventricular tachycardia despite regular drug intake and adequate dosages. Blood levels were not available.
In the prospective part of data analysis, patients with
inducible ventricular tachycardia underwent antiarrhythmic drug testing guided by serial programmed
ventricular stimulation. Drug efficacy was judged according to criteria previously reported34 and shown in
Figure 1. In patients with noninducible ventricular
tachycardia, drug therapy was guided by repeated 48hour Holter monitoring and symptom-limited treadmill
exercise tests. The efficacy criteria used for analysis are
shown in Figure 2.
Follow-up
End points for follow-up were either spontaneous
recurrences of ventricular tachycardia or sudden death
TABLE 3. Drugs and Dosages Used in Patients With Inducible
Ventricular Tachycardia
No. of
Dosage (mg/day)
patients
Class
Drug
594±138
10
Ia
Disopyramide
600
1
Quinidine
800
1
Tocainide
Ib
16
700± 135
Mexiletine
728±196
20
Ic
Propafenone
250±50
17
Flecainide
113±23
8
Aprindine
107±41
7
Prajmaline
333±153
3
Lorcainide
1
600
Diprafenone
450
1
Barucainide
38
459±100
Sotalol
III
13
400±155*
Amiodarone
5
300±120
IV
Verapamil
*After a loading phase of 1000 mg/day for 21 days.
Values are given as mean+SD.
31
TABLE 4. Drugs and Dosages Used in Patients With Noninducible Ventricular Tachycardia
No. of
Dosage (mg/day)
patients
6
480± 130
2
600+0
5
1,400±283
Ib
13
600±85
19
644± 174
Ic
13
227±65
100
1
Aprindine
67±12
5
Prajmaline
3
300±150
Diprafenone
III
35
440±69
Sotalol
4
533±115*
Amiodarone
IV
24
371±79
Verapamil
*After a loading phase of 1,000 mg/day for 21 days.
Values are given as mean±SD.
Class
Ia
Drug
Disopyramide
Quinidine
Tocainide
Mexiletine
Propafenone
Flecainide
and cardiac or noncardiac death or the time of study
closure. No patient was lost to follow-up. In patients
who discontinued electrophysiologically or clinically
tested and effective antiarrhythmic drug therapy, follow-up ended at the time of drug withdrawal. The
follow-up data were obtained by regular follow-up visits
at our institution and telephone contact with the patients and their physicians at regular intervals.
Results
Results of Control Electrophysiological Study
During the control electrophysiological study, 42 of
81 patients (36 men; mean age at diagnosis, 38±14.5
years) had inducible sustained ventricular tachyarrhythmias (monomorphic ventricular tachycardia, n=39
[92.8%]; mean cycle length, 291±71 msec [190-530
msec]; polymorphic ventricular tachycardia, n = 1
[2.4%]; ventricular fibrillation, n=2 [4.8%]). These ventricular tachyarrhythmias were induced from the right
ventricular apex in 37 patients (88.1%) and from the
right ventricular outflow tract in the remaining five
patients (11.9%). Their induction required single extrastimuli in six patients (14.3%), double in 31 (73.8%),
triple in five (11.9%), and isoprenaline infusion in four
VT iduciblity during PVS compared to bascline
none
more difficult
unc ange
(:;p2 steps in basic drive)
I
Icomp.letcsuppressson
IPaponsI
drug failure
FIGURE 1. Chart of criteria of drug efficacy in patients with
inducible ventricular tachycardia (VT). A response to a drug
was considered to be present if VT was no longer inducible or
rendered more difficult to induce. Drug failure was present if
there was unchanged inducibility or a spontaneous recurrence
of VT. PVS, programmed ventricular stimulation.
32
Circulation Vol 86, No 1 July 1992
48 hour Holter and
xercise tests
sVTw v- J
<100%
100%
coupu~PVCB
>70%
<70%reduction
|completearth reppesson
failure
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
FIGURE 2. Chart of criteria of drug efficacy in patients with
noninducible ventricular tachycardia (VT). Complete suppression was defined as abolition of sustained VT (sVT),
nonsustained VT (nsVT), and ventricular runs (v-runs). A
partial response was present if v-runs were not completely
abolished. Drugfailure was present if either there was a < 70%
reduction in v-runs, couplets, or premature ventricular complexes (PVCs) or a spontaneous recurrence of VT.
of 42 patients (9.5%). Ventricular tachyarrhythmias
terminated by ventricular extrastimuli in eight
patients (19.5%), overdrive pacing in 25 patients
(61.0%), or cardioversion in five patients (12.2%). In
the remaining three patients (7.3%), ventricular tachycardia terminated spontaneously after 95+± 78 seconds
(range, 40-150 seconds).
In 39 of 81 patients (14 men; mean age, 40±13 years),
no sustained ventricular tachyarrhythmia was inducible
during programmed ventricular stimulation including
isoprenaline provocation. In nine patients (23.1%),
nonsustained (n=4) or sustained (n=5) ventricular
tachyarrhythmias occurred spontaneously during administration of intravenous isoprenaline infusion.
were
Efficacy of Antiarrhythmic Drugs in Inducible
Ventricular Tachycardia
Acute response. In 42 patients with inducible ventricular tachycardia, a total of 174 drug tests were performed (Table 5). Prospective analysis of drug efficacy
included 128 drug tests in these 42 patients, whereas the
remaining 46 drug tests were evaluated retrospectively
in 20 patients.
Sotalol treatment resulted in the highest overall effirate (68.4%). Complete suppression was achieved
in 22 of 38 patients (57.9%), and partial response was
achieved in another four patients (10.5%). In only three
of 12 patients not responding to monotherapy with oral
sotalol, ventricular tachycardia induction was suppressed completely by amiodarone (n = 1) or a combination of sotalol with class I agents (n=2), whereas the
remaining nine patients proved drug refractory after
serial testing with 3.8±2.3 drugs, including amiodarone
in five cases. Nonpharmacological therapy was performed in eight of these patients. The remaining patient
was discharged on sotalol despite persistent ventricular
tachycardia induction.
Amiodarone proved to be effective according to the
electrophysiological criteria in only two of 13 patients
(15.4%). Ventricular tachycardia induction was unchanged in nine patients, six of whom had spontaneous
ventricular tachycardia recurrences after 7±7 months
(range, 1-18 months) during a total follow-up of 17±19
months (range, 1-51 months). The remaining two patients were followed clinically without programmed
ventricular stimulation after the loading phase. Both
had spontaneous ventricular tachycardia relapses after
3 and 12 months, respectively, and amiodarone treatment was discontinued.
Class Ia and lb drugs as well as class Ic agents were
effective in only 5.6% and 12.0%, respectively. Because
several patients received more than one drug of the
same group, the total number of drug tests exceeded the
number of patients. Only one of 28 tests (3.6%; disopyramide) performed with class Ia or lb drugs and three of
57 tests (5.3%; flecainide, propafenone, aprindine) with
class Ic agents were successful.
}3-Blockers (n=7) and verapamil (n=5) failed in all
patients treated.
Drug combinations were effective in four of 26 patients (15.4%) in whom the individual agents had previously failed. Combinations of class I drugs with sotalol
(n=10) or amiodarone (n=4) were effective in two
patients each, whereas combinations of two class I drugs
(n=5) or class I drugs with P-blockers (n=7) showed no
beneficial effect.
Follow-up. Thirty-one of 42 patients (73.8%) with
inducible ventricular tachycardia were discharged on
pharmacological treatment guided by serial drug testing, whereas the remaining 11 patients (26.2%) were
cacy
TABLE 5. Efficacy of Antiarrhythmic Drugs in Patients With Inducible Ventricular Tachycardia
Drug
Class Ia/b
Class Ic
3-Blockers
Sotalol
Amiodarone
Verapamil
Combinations
Two class I drugs
Class I+/3-blocker
Class I+sotalol
Class I+amiodarone
No. of
patients
18
25
7
38
13
5
26
5
7
10
4
Overall efficacy
No.
S
1
5.6
3
12.0
0
0
26
68.4
2
15.4
0
0
4
15.4
0
0
0
0
2
20.0
2
50.0
Complete suppression
No.
S
0
0
1
4.0
Partial response
No.
S
1
5.6
2
8.0
22
2
57.9
15.4
4
0
10.5
0
2
7.7
2
7.7
0
2
0
50.0
2
0
20
0
Wichter et al Antiarrhythmic Drug Efficacy in ARVD
33
TABLE 6. Efficacy of Antiarrhythmic Drugs in Patients With Noninducible Ventricular Tachycardia
Drug
Class Ia/b
Class Ic
,B-Blockers
Sotalol
Amiodarone
Verapamil
Combinations
Two class I drugs
Class I+3-blocker
Class I+sotalol
Class I+amiodarone
No. of
patients
16
23
7
35
4
24
11
1
5
3
2
Overall efficacy
No.
%
0
0
4
17.4
2
28.6
29
82.8
1
25.0
12
50.0
1
9.1
0
0
0
0
0
0
1
50.0
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
considered drug refractory and were treated with alternative modalities such as catheter ablation (n=9), antitachycardia surgery (n =1), or implantation of a cardioverter-defibrillator (n = 1). At the time of discharge, 21
patients received oral sotalol alone, and four patients
received sotalol in combination with a class I drug
(aprindine, n=3; mexiletine, n= 1). The remaining six
patients were treated with amiodarone (n =2), class Ic
drugs (n=2; propafenone, flecainide), or a combination
of amiodarone and class Ic drugs (n=2; propafenone,
flecainide). During a mean follow-up of 34±25 months
(range, 2-103 months), there were no sudden cardiac
deaths or cardiac or noncardiac deaths in these 31
patients discharged on pharmacological therapy. Three
patients (9.7%) had nonfatal recurrences of ventricular
tachycardia after 0.5, 51, and 63 months, one of which
was associated with hypokalemia.
Efficacy of Antiarrhythmic Drugs in Noninducible
Ventricular Tachycardia
Acute response. In 39 patients with noninducible ventricular tachycardia, a total of 148 drug tests were
performed (Table 6). Prospective analysis of drug efficacy included 91 drug tests in these 39 patients, whereas
the remaining 57 drug tests were evaluated retrospectively in 17 patients.
The overall efficacy rate for sotalol was 82.8% with a
complete suppression of frequent ventricular runs and
nonsustained or sustained ventricular tachycardia in 23
of 35 patients (65.7%) and a partial response in an
additional six patients (17.1%). Only one of four patients was effectively treated with amiodarone. 1-Blockers showed a partial effect in two of seven patients
(28.6%), and verapamil was effective in 12 of 24 patients
(50.0%), half of them meeting the criteria of complete
arrhythmia suppression. Class Ia and Ib antiarrhythmic
drugs were not effective in any of 16 patients (total
number of drug tests, 26), whereas class Ic agents were
effective in four of 23 patients (17.4%) in a total number
of 41 drug tests (9.8% effective tests; propafenone, n=2;
flecainide, n=2). Drug combinations showed partial
response in one of 11 patients (9.1%; amiodarone with
flecainide) despite previous failure of the individual
drugs.
Follow-up. At the time of discharge, 33 of 39 patients
(84.6%) with noninducible ventricular tachycardia were
treated pharmacologically. Twenty-four patients re-
Complete suppression
S
No.
Partial response
No.
%
1
0
23
0
7
0
4.4
0
65.7
0
29.2
0
3
2
6
1
5
1
13.0
28.6
17.1
25.0
20.8
9.1
0
0
1
50.0
ceived oral sotalol, seven patients received verapamil,
and two patients received class Ic agents (propafenone,
flecainide). Two patients with clinically asymptomatic
short ventricular runs were discharged without treatment. Both are doing well after 6 and 21 months of
follow-up. The remaining four patients with symptomatic ventricular tachycardia did not respond to pharmacological treatment and underwent catheter ablation.
During a mean follow-up of 14±13 months (range,
2-65 months), there were no sudden cardiac deaths and
no cardiac or noncardiac deaths in these 33 patients
discharged on antiarrhythmic drug therapy. Four patients (12.1%) had nonfatal recurrences of ventricular
tachycardia. Recurrences occurred in two of 24 patients
(8.3%) discharged on sotalol and in two of seven
patients (28.6%) discharged on verapamil. At the time
of discharge, drug therapy had been judged as completely effective in three of them and partially effective
in the remaining patient.
Side Effects
During treatment with class I drugs, gastrointestinal
side effects demanded discontinuation of therapy in five
of 54 patients (9.3%) or five of 152 drug tests (3.3%).
Sotalol had to be withdrawn in four of 73 patients
(5.5%) because of symptomatic bradycardia (n= 1),
hypotension (n=l), pulmonary congestion (n=1), and
QT prolongation with torsade de pointes (n = 1). Atrioventricular conduction disturbances were not observed.
In all except one patient, side effects occurred during
the first days of therapy during hospital stay. Thus,
during a total follow-up of 25+±22 months, only one of
49 patients discharged on sotalol developed serious side
effects (symptomatic hypotension) after discharge. Amiodarone treatment was discontinued in five of 17 patients (29.4%) because of serious side effects (hyperthyroidism, n=3; hepatotoxicity, n=1; ophthalmic toxicity
with symptomatic corneal deposits, n=1) during longterm therapy after 24±+ 24 months (range, 2-51
months). No serious adverse effects were observed
during treatment with 8-blockers or verapamil.
Discussion
Ventricular tachyarrhythmias are the major clinical
manifestation of arrhythmogenic right ventricular disease. The documented arrhythmia may range from
frequent premature ventricular complexes, ventricular
34
Circulation Vol 86, No 1 July 1992
runs, and nonsustained ventricular tachycardia to sustained ventricular tachycardia.12'36,37 Primary ventricular fibrillation has been reported in single cases but
appears to be rare.38-41 The right ventricular origin of
the arrhythmias is suggested by the left bundle branch
block morphology of ventricular tachycardia and can be
confirmed by detailed endocardial catheter mapping
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
techniques.
Although some patients do not report any symptoms
suggestive of arrhythmias, the majority of patients present clinically with either palpitations, dizziness, syncope, or even sudden death. Patients with inducible
ventricular tachycardia during programmed ventricular
stimulation normally present with spontaneous sustained monomorphic ventricular tachycardia. They frequently exhibit pronounced global or regional right
ventricular contraction abnormalities detectable by various imaging techniques. In contrast, patients with noninducible ventricular tachycardia normally present with
repetitive ventricular runs or nonsustained ventricular
tachycardia and only mild or moderate right ventricular
contraction abnormalities, which may only be detectable
by biplane right ventricular angiography.12-'5 However,
due to the variable appearance of a normal right
ventricle, differentiation of abnormal from normal right
ventricular contractions may be difficult in patients with
very mild angiographic findings. Because circumscribed
right ventricular contraction abnormalities do not necessarily result in a reduction of global right ventricular
function, the right ventricular ejection fraction is within
normal limits in most patients with noninducible ventricular tachycardia.
The need for antiarrhythmic therapy has been advocated in both subgroups of arrhythmogenic right ventricular disease because of symptoms and possibly prognostic aspects since sudden cardiac death may occur in
both patient groups.16"7 However, specific risk factors
for the selection of patients at high risk of sudden
cardiac death have not been defined. The experiences
with the use of antiarrhythmic drugs in patients with
coronary artery disease or cardiomyopathies are not
necessarily transferable to patients with arrhythmogenic
right ventricular disease. Because information on the
use of antiarrhythmic drugs in these patients is limited,
this study was performed to analyze and discuss the
short- and long-term effects of antiarrhythmic drug
therapy in 81 patients with arrhythmogenic right ventricular disease.
Overall, 64 of 81 patients (79.0%) who were referred
for further treatment, responded acutely to antiarrhythmic drug therapy without limiting side effects, whereas
15 patients (18.5%) were subjected to nonpharmacological therapy, and two patients (2.5%) were discharged
without treatment.
Class I antiarrhythmic drugs have been demonstrated
to be effective during electrophysiological testing in the
treatment of life-threatening ventricular tachyarrhythmias in various underlying heart diseases. Most available data refer to postmyocardial infarction ventricular
tachyarrhythmias and less frequently to patients with
dilative cardiomyopathy.42-45 However, in patients with
arrhythmogenic right ventricular disease, varying results
have been reported.13"14'19,2' In our patients with inducible as well as noninducible ventricular tachycardia,
class I antiarrhythmic drugs proved effective in only a
minority of patients. Effective treatment with class I
agents was achieved in only four of 85 drug tests (4.7%)
performed in 27 patients with inducible ventricular
tachycardia and in only five of 67 drug tests (7.5%) in 27
patients with noninducible ventricular tachycardia. The
overall efficacy rates were 14.8% and 18.5% of patients,
respectively, markedly lower than those reported in the
treatment of ischemic ventricular tachycardia, although
various class I agents were tested, and some patients
received three or more different class I drugs successively without satisfactory therapeutic effect. Class Ic
agents appeared to be slightly more effective than class
Ia and Ib drugs; this has also been reported by
others.45,46
,B-Blockers, which were tested in only a small group of
patients, did not have sufficient antiarrhythmic effect in
those with inducible ventricular tachycardia but were at
least partially effective in a small number of patients
with noninducible ventricular tachycardia (28.6%). This
corresponds to studies in patients with idiopathic ventricular tachycardia, possibly by an inhibition of catecholamine-induced increase of intracellular cyclic AMP
mediated by GTP-dependent regulatory proteins.4749
Our results demonstrate that oral sotalol administered in dosages ranging from 320 to 480 mg/day (up to
640 mg/day in selected cases) appears to be the most
effective antiarrhythmic drug in the treatment of both
inducible and noninducible ventricular tachycardia in
arrhythmogenic right ventricular disease. The overall
efficacy rates were 68.4% and 82.8%, respectively. Side
effects demanding withdrawal of sotalol treatment were
rare (5.5%) and mostly occurred within the first days of
therapy. High efficacy rates of sotalol compared with
other antiarrhythmic agents may not be unique in the
condition of arrhythmogenic right ventricular disease
because similar overall efficacy rates of 61% were
observed in our group of 171 patients with inducible
ventricular tachycardia and various underlying heart
diseases (68% coronary artery disease).50 Serious side
effects were observed in only nine of these 171 patients
(5.3%) despite considerably high dosages of sotalol,
which also confirms the low rate of adverse effects
reported in the present study. Sotalol dosages of more
than 320-480 mg/day clearly exceed the dosage necessary for pl-blockade,5' so that its antiarrhythmic efficacy
may predominantly be attributed to its class III activity.
All except one patient with inducible ventricular tachycardia not responding to oral sotalol or combinations
with sotalol proved refractory against all other antiarrhythmic agents tested (including amiodarone). Therefore, nonpharmacological therapy without further serial
drug testing should be considered in sotalol nonresponders with inducible ventricular tachycardia.
Amiodarone did not seem to be superior to sotalol.
Of 12 patients receiving both drugs successively, one of
eight sotalol nonresponders was effectively treated with
amiodarone, whereas two of nine amiodarone nonresponders were effectively treated with sotalol. With
regard to its potential side effects during long-term
therapy,52 amiodarone does not appear to be the drug of
first choice in the treatment of young patients requiring
long-term antiarrhythmic drug therapy.
Verapamil has been reported to be effective in a
considerable percentage of patients with various forms
of nonischemic ventricular tachycardia, especially right
Wichter et al Antiarrhythmic Drug Efficacy in ARVD
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
ventricular outflow tract tachycardia.19,20,53-57 In our
study group, 50% of patients with noninducible ventricular tachycardia responded to verapamil, and 92% of
them met the criteria of repetitive nonsustained ventricular tachycardia originating in the right ventricular
outflow tract. The mechanism of these tachycardias is
postulated to be due to catecholamine-induced delayed
afterdepolarizations dependent on intracellular calcium
overload. Adenosine appears to be highly effective in
specifically inhibiting cyclic AMP through an inhibitory
G protein and therefore is effective only in the termination of ventricular tachycardia due to cyclic AMPmediated triggered activity. By blocking the slow-inward
calcium current and therefore preventing intracellular
calcium overload, verapamil is effective in calciuminduced, ouabain-induced, and catecholamine-cyclic
AMP-mediated triggered activity.47,58 Only a few of our
patients with inducible ventricular tachycardia received
verapamil, which does not permit any definite conclusions. However, none of the patients in this group
responded to verapamil.
A combination of antiarrhythmic drugs may result in
electrophysiological and antiarrhythmic properties that
may be different from the actions of the individual
agents. Drug combination may cause enhanced or decreased antiarrhythmic efficacy but also may increase or
decrease the incidence of side effects, depending on the
dosage of the individual drugs.59-M In this regard, our
experience with antiarrhythmic drug combinations in
patients with arrhythmogenic right ventricular disease is
limited. These limited observations in patients on combination therapy did not appear to be promising. Drug
combinations with class I drugs and amiodarone or
sotalol were effective in a minority of patients in whom
the individual drugs had previously failed, whereas
combinations of two class I drugs and class I drugs with
p3-blockers were not effective in any of the patients
treated. This contrasts with the results of French authors who reported satisfactory therapeutic effects of
combined therapy with class I agents and p-blockers.23
Our experience in the use of drug combinations with
amiodarone is supported by the same authors who also
found an increase of amiodarone efficacy by additional
therapy with class I drugs in single patients. The combination of amiodarone with p-blockers may be more
effective than the individual drugs.22'23 In a study by
Leclercq et al,23 all of the six patients previously insufficiently treated by class I agents, amiodarone, or
p-blockers alone or by combinations of class I agents
with p-blockers or amiodarone proved to be effectively
treated with the combination of amiodarone and
p-blockers. These observations should be viewed in the
light of our positive results with high dosages of sotalol.
Both therapeutic regimen consist in a combination of
class III and p-blocking antiarrhythmic properties,
which appears to act synergistically in patients with
arrhythmogenic right ventricular disease. This may be
due to the strong catecholamine dependence as a
triggering factor for ventricular arrhythmia in many of
these patients, uncovered by stress tests or isoprenaline
infusion.65-68
The low incidence of recurrences of ventricular tachyarrhythmias and the absence of sudden deaths during
follow-up of our patients with inducible ventricular
tachycardia who were discharged on drugs considered
35
effective confirms the predictive value of electrophysiologically controlled serial drug testing. Although there
have been no studies on the reproducibility of programmed ventricular stimulation in arrhythmogenic
right ventricular disease, our results indicate that electrophysiological study and successful serial drug testing
may select patients at lower risk of sudden cardiac
death. Of the 11 patients with drug-refractory inducible
ventricular tachycardia, one patient with multiple origins of right ventricular tachycardia and a progressive
and extensive form of arrhythmogenic right ventricular
dysplasia died suddenly 3 months after successful repeated catheter ablation.
In patients with noninducible ventricular tachycardia,
serial drug testing controlled by Holter monitoring and
exercise testing may be sufficiently safe, provided there
is no history of life-threatening events. In case of
survived cardiac arrest or recurrent syncope and noninducibility of ventricular tachyarrhythmia, the implantation of a cardioverter-defibrillator should be considered.
Recurrences of ventricular tachycardia may not necessarily reduce the reliability of electrophysiologically
or Holter controlled serial drug testing because they
also may be due to metabolic abnormalities (such as
hypokalemia in one of our patients) or progression of
the underlying disease. The latter should especially be
considered in case of late recurrences during long-term
follow-up of arrhythmogenic right ventricular disease.
Study Limitations
To our knowledge, this is the first large-scale report
on the effect of various antiarrhythmic drugs in arrhythmogenic right ventricular disease. However, several
limitations of the present study should be addressed.
The study was a nonrandomized, partly retrospective
analysis of drug efficacy. All available information concerning previous antiarrhythmic drug therapy was prospectively documented, but the decision to treat a
patient with a given antiarrhythmic drug was based on
clinical grounds that were sometimes arbitrary. The
data may be biased by the selection of drugs during
serial antiarrhythmic testing in our institution since the
favorable response to sotalol later resulted in a first-line
application of this specific drug in the treatment of
patients with arrhythmogenic right ventricular disease.
As drug administration was not randomized, this may
have influenced the efficacy rates in this study. In
addition, there was no standard antiarrhythmic drug
dosing, and blood levels usually were not available.
Furthermore, most of the patients were referred to our
department for further antiarrhythmic treatment of
severe symptoms and were preselected insofar as many
had undergone previous antiarrhythmic drug therapy
that had failed. With the exception of verapamil, differences between the two patient groups concerning the
response rates to antiarrhythmic drugs may be due at
least in part to the methods of drug testing used in this
study. Patients with inducible ventricular tachycardia
were evaluated using the more rigorous method of serial
electrophysiologic testing, which may have resulted in
lower efficacy rates compared with patients with noninducible ventricular tachycardia in whom drug testing
was controlled by repeated Holter and exercise tests.
36
Circulation Vol 86, No 1 July 1992
Clinical Implications
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
The low recurrence rates of ventricular tachycardia and
the absence of sudden death during long-term follow-up
of patients after successful serial drug testing indicates the
predictive value of electrophysiologically guided serial
drug testing in patients with arrhythmogenic right ventricular disease and inducible ventricular tachycardia. In
patients with noninducible ventricular tachycardia, serial
drug testing guided by repeated Holter and exercise tests
may be sufficiently safe, provided there is no history of
life-threatening arrhythmias necessitating the implantation of a cardioverter-defibrillator.
Oral sotalol may be a first-line antiarrhythmic agent
in the treatment of both inducible and noninducible
ventricular tachycardia in patients with arrhythmogenic
right ventricular disease. Patients with inducible ventricular tachycardia not responding to sotalol are likely
to prove to be drug refractory and may be candidates for
early nonpharmacological therapy without extensive serial drug testing. Amiodarone did not prove to be more
effective than sotalol and may not be an alternative
because of frequent side effects during long-term therapy. ,3-Blockers and verapamil may be an alternative in
the treatment of noninducible ventricular tachycardia in
arrhythmogenic right ventricular disease. Class I antiarrhythmic drugs appear to be rarely effective in both
inducible and noninducible ventricular tachycardias of
right ventricular origin. A prospective randomized study
has been started to further elucidate and confirm these
results.
References
1. Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL,
Malergue C, Grosgogeat Y: Right ventricular dysplasia: A report
of 24 cases. Circulation 1982;65:384-398
2. Wichter T, Borggrefe M, Breithardt G: Die arrhythmogene rechtsventrikulare Erkrankung. Z Kardiol 1991;80:107-125
3. Breithardt G, Borggrefe M, Wichter T: Editorial comment: Catheter ablation of idiopathic right ventricular tachycardia. Circulation
1990;82:2273-2276
4. Rizzon P, Breithardt G, Chiddo A: Arrhythmogenic right ventricle.
Eur Heart J 1989;10(suppl D)
5. Blomstrom-Lundqvist C: The Syndrome of Arrhythmogenic Right
Ventricular Dysplasia-Diagnostic and Prognostic Implications (thesis). Goteborg, University of G6teborg, 1987
6. Fontaine G, Fontaliran F, Linares-Cruz E, Chomette G, Grosgogeat Y: The arrhythmogenic right ventricle, in Iwa T, Fontaine G
(eds): Cardiac Arrhythmias: Recent Progress in Investigation and
Management. New York, Elsevier Science Publishers BV, 1988,
pp 189-202
7. Strain JE: Adipose dysplasia of the right ventricle: Is endomyocardial biopsy useful? Eur Heart J 1989;10(suppl D):84-88
8. Strain JE, Grose RM, Factor SM, Fisher JD: Results of endomyocardial biopsy in patients with spontaneous ventricular tachycardia but without apparent structural heart disease. Circulation 1983;
68:1171-1181
9. Wichter T, Auffermann W, Breithardt G, Borggrefe M, Bongartz
G, Peters PE: Magnetic resonance imaging in arrhythmogenic right
ventricular disease. (abstract) Eur Heart J 1989;10(suppl):13
10. Casolo AC, Poggesi L, Boddi M, Fazi A, Bartolozzi C, Lizzadro G,
Dabizzi RP: ECG-gated magnetic resonance imaging in right ventricular dysplasia. Am Heart J 1987;114:1245-1248
11. Klersy C, Raisaro A, Salerno JA, Montemartini C, Campani R:
Arrhythmogenic right and left ventricular disease: Evaluation by
computed tomography and nuclear magnetic resonance imaging.
Eur Heart J 1989;10(suppl D):33-36
12. Martini B, Nava A, Thiene G, Buja GF, Canciani B, Miraglia G,
Scognamiglio R, Boffa GM, Daliento L: Accelerated idioventricular rhythm of infundibular origin in patients with a concealed form
of arrhythmogenic right ventricular dysplasia. Br Heart J 1988;59:
564-571
13. Palileo EV, Ashley WW, Swiryn S, Bauernfeind RA, Strasberg B,
Petropoulos AT, Rosen KM: Exercise provocable right ventricular
outflow tract tachycardia. Am Heart J 1982;104:185-192
14. Buxton AE, Waxman HL, Marchlinski FE, Simson MB, Cassidy D,
Josephson ME: Right ventricular tachycardia: Clinical and electrophysiological characteristics. Circulation 1983;68:917-927
15. Proclemer A, Ciani R, Feruglio GA: Right ventricular tachycardia
with ventricular dysplasia: Clinical features, diagnostic techniques,
and current management. Am Heart J 1989;103:415-420
16. Rowland TW, Schweiger MJ: Repetitive paroxysmal ventricular
tachycardia and sudden death in a child.AmJ Cardiol 1984;53:1729
17. Blomstrom-Lundqvist C, Sabel KG, Olsson B: A long term follow
up of 15 patients with arrhythmogenic right ventricular dysplasia.
Br Heart J 1987;58:477-488
18. Borggrefe M, Breithardt G: Beneficial effects of sotalol in patients
with right ventricular dysplasia and drug-refractory ventricular
tachycardia. Circulation 1985;72(suppl lII):III-1768
19. Wichter T, Borggrefe M, Martinez-Rubio A, Hief C, Breithardt G:
Arrhythmogenic right ventricular disease: Antiarrhythmic drug
therapy in patients with inducible and non-inducible ventricular
tachycardia. Circulation 1990;82(suppl III):III-435
20. Woelfel A, Foster JR, McAllister RG Jr, Simpson RJ Jr, Gettes
LS: Efficiacy of verapamil in exercise-induced ventricular tachycardia. Am J Cardiol 1985;53:751-756
21. Lemery R, Brugada P, Della Bella P, Dugernier T, van den Dool
A, Wellens HJJ: Nonischemic ventricular tachycardia: Clinical
course and long-term follow-up in patients without clinically overt
heart disease. Circulation 1989;79:990-999
22. Tonet J, Frank R, Fontaine G, Grosgogeat Y: Efficacite de l'association de faibles doses de beta-bloquants a lamiodarone dans le
traitment des tachycardies ventriculaires refractaires. Arch Mal
Coeur 1989;82:1511-1517
23. Leclercq JF, Coumel P: Characteristics, prognosis and treatment of
the ventricular arrhythmias of right ventricular dysplasia. Eur Heart
J 1989;10(suppl D):61-67
24. Chiddo A, Locuratolo N, Gaglione A, Bortone A, Troito G, Musci
S, Grimaldi N, Rizzon P: Right ventricular dysplasia: Angiographic
study. Eur Heart J 1989;10(suppl D):42-45
25. Daubert C, Descaves C, Foulgoc JL, Bourdonnec C, Laurent M,
Gouffault J: Critical analysis of cineangiographic criteria for diagnosis of arrhythmogenic right ventricular dysplasia. Am Heart J
1988;115:448-459
26. Daliento L, Rizzoli G, Thiene G, Nava A, Rinuncini M, Chioin R,
Dalla Volta S: Diagnostic accuracy of right ventriculography in
arrhythmogenic right ventricular cardiomyopathy. Am J Cardiol
1990;66:741-745
27. Blomstrom-Lundqvist C, Selin K, Jonsson R, Johannson SR,
Schlossman D, Olsson SB: Cardioangiographic findings in patients
with arrhythmogenic right ventricular dysplasia. Br Heart 1 1988;
59:556-563
28. Blomstrom-Lundqvist C, Beckmann-Suurkula M, Wallentin I,
Jonsson R, Olsson SB: Ventricular dimensions and wall motion
assessed by echocardiography in patients with arrhythmogenic
right ventricular dysplasia. Eur Heart J 1988;9:1291-1302
29. Foale RA, Nihoyannopoulos P, Ribeiro P, McKenna WJ, Oakley
CM, Krikler DM, Rowland E: Right ventricular abnormalities in
ventricular tachycardia of right ventricular origin: Relation to electrophysiological abnormalities. Br Heart J 1986;56:45-54
30. Scognamiglio R, Fasoli G, Nava A, Miraglia G, Thiene G, DallaVolta S: Contribution of cross-sectional echocardiography to the
diagnosis of right ventricular dysplasia at the asymptomatic stage.
Eur Heart J 1989;10:538-542
31. Kisslo J: Two-dimensional echocardiography in arrhythmogenic
right ventricular dysplasia. Eur Heart J 1989;10(suppl D):22-26
32. Robertson JH, Bardy GH, German LD, Gallagher JJ, Kisslo J:
Comparison of two-dimensional echocardiographic and angiographic findings in arrhythmogenic right ventricular dysplasia. Am
J Cardiol 1985;55:1506-1508
33. Boak JG, Bove AA, Kreulen T, Spann JF: A geometric basis for
the calculation of right ventricular volume in man. Cathet Cardiovasc Diagn 1977;3:217-230
34. Borggrefe M, Trampisch HJ, Breithardt G: Reappraisal of criteria
for assessing drug efficacy in patients with ventricular tachyarrhythmias: Complete versus partial suppression of inducible arrhythmias. JAm Coil Cardiol 1988;12:140-149
35. Vaughan-Williams EM: Classification of antiarrhythmic drugs, in
Sandoe E, Flensted-Jensen E, Olesen K (eds): Cardiac Arrhythmias. S0destalje, Sweden, AD Astra, 1970, pp 449-473
Wichter et al Antiarrhythmic Drug Efficacy in ARVD
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
36. Rossi P, Massumi A, Gillette P, Hall RJ: Arrhythmogenic right
ventricular dysplasia: Clinical features, diagnostic techniques and
current management. Am Heart J 1982;103:415-420
37. Reiter MJ, Smith WM, Gallagher JJ: Clinical spectrum of ventricular tachycardia with left bundle branch morphology. Am J Cardiol
1983;51:113-121
38. Belhassen B, Shapira I, Hammerman C: Unusual manifestations of
arrhythmogenic right ventricular dysplasia as ventricular fibrillation, atrial paralysis, and hypoexcitable right ventricle. Br Heart J
1988;59:263-265
39. Martini B, Nava A, Thiene G, Buja GF, Canciani B, Scognamiglio
R, Daliento L, Dalla Volta S: Ventricular fibrillation without
apparent heart disease: Description of six cases. Am Heart J 1989;
118:1203-1209
40. Olsson SB, Edvardsson N, Emanuelsson H, Enestrom S: A case of
arrhythmogenic right ventricular dysplasia with ventricular fibrillation. Clin Cardiol 1982;5:591
41. Rizzon P: Polymorphism of the clinical picture. Eur Heart J 1989;
10(suppl D):10-12
42. Waller TJ, Kay HR, Spielman SR, Kutalek SP, Greenspan AM,
Horowitz LN: Reduction in sudden death and total mortality by
antiaarrhythmic therapy evaluated by electrophysiologic drug testing: Criteria of efficacy in patients with sustained ventricular tachycardia. JAm Coll Cardiol 1987;10:83-89
43. Hernandez M, Reder RF, Marinchak RA, Rials SJ, Kowey PR:
Propafenone for malignant ventricular arrhythmia: An analysis of
the literature. Am Heart J 1991;121:1178-1184
44. Budde T, Borggrefe M, Podczeck A, Martinez-Rubio A, Breithardt
G: Acute and long-term efficacy of oral propafenone in patients
with ventricular tachyarrhythmias. J Cardiovasc Pharmacol 1991;
18:254-260
45. Horowitz LN, Morganroth J: Second generation antiarrhythmic
agents: Have we reached antiarrhythmic nirvana? JAm Col] Cardiol 1987;9:459-463
46. Pottage A: Clinical profiles of newer class 1 antiarrhythmic
agents-tocainide, mexiletine, encainide, flecainide and lorcainide.
Am J Cardiol 1983;52:24C-31C
47. Lerman BB, Belardinelli L, West A, Berne RM, DiMarco JP:
Adenosine-sensitive ventricular tachycardia: Evidence suggesting
cyclic AMP-mediated triggered activity. Circulation 1986;74:
270-280
48. DiCarlo LA Jr, Susser F, Winston SA: The role of P-blockade
therapy for ventricular tachycardia induced with isoproterenol: A
prospective analysis. Am Heart J 1990;120:1347-1355
49. Brodsky MA, Allen BJ, Luckett CR, Capparelli EV, Wolff LJ,
Henry WL: Antiarrhythmic efficacy of solitary beta-adrenergic
blockade for patients with sustained ventricular tachyarrhythmias.
Am Heart J 1989;118:272-280
50. Martinez-Rubio A, Chen X, Hief C, Buscher A, Borggrefe M,
Breithardt G: Acute and long-term efficacy of sotalol in patients
with ventricular tachyarrhythmias. (abstract) Eur Heart J 1990;
11(suppl):242
51. Nattel S, Feder-Elituv R, Matthews C, Nayebpour M, Talajic M:
Concentration dependence of class 3 and beta-adrenergic blocking
37
effects of sotalol in anesthetized dogs. JAm Coil Cardiol 1989;13:
1190-1194
52. Herre JM, Sauve MJ, Malone P, Griffin JC, Helmy I, Landberg JJ,
Goldberg H, Scheinman MM: Long-term results of amiodarone
therapy in patients with recurrent sustained ventricular tachycardia or ventricular fibrillation. JAm Coil Cardiol 1989;13:442-449
53. Mason JW, Swerdlow CD, Mitchell LB: Efficiacy of verapamil in
chronic recurrent ventricular tachycardia. Am J Cardiol 1983;51:
1614-1617
54. Akhtar M, Tchou P, Jazayeri M: Use of calcium channel entry
blockers in the treatment of cardiac arrhythmias. Circulation 1989;
80(suppl IV):IV-31-IV-39
55. Belhassen B, Horowitz LN: Use of intravenous verapamil for ventricular tachycardia. Am J Cardiol 1984;54:1131-1133
56. Strasberg B, Kusniec J, Lewin RF, Sclarovsky S, Arditti A, Agmon
J: An unusual ventricular tachycardia responsive to verapamil. Am
Heart J 1986;111:190-192
57. Wu D, Kou HC, Hung FS: Exercise-triggered paroxysmal ventricular tachycardia: A repetitive rhythmic activity possibly related to
afterdepolarization. Ann Intern Med 1981;95:410-414
58. Lerman BB, Berlardinelli L: Cardiac electrophysiology of adenosine. Circulation 1991;83:1499-1509
59. Mendes L, Podrid PJ, Fuchs T, Franklin S: Role of combination
drug therapy with a class lc antiarrhythmic drug and mexiletine for
ventricular tachycardia. JAm Coll Cardiol 1991;17:1396-1402
60. Patt MV, Grossbard CL, Graboys TB, Lown B: Combination antiarrhythmic therapy for management of malignant ventricular
arrhythmia. Am J Cardiol 1988;62:181-211
61. Levy S: Combination therapy for cardiac arrhythmias. Am J Cardiol
1988;61:95A-1O1A
62. Ross DL, Sze DY, Keefe DL, Swerdlow CD, Echt DS, Griffin JC,
Winkle RA, Mason JW: Antiarrhythmic drug combinations in the
treatment of ventricular tachycardia: Efficacy and electrophysiologic effects. Circulation 1982;66:1205-1210
63. Greenspan AM, Spielman SR, Horowitz LN: Combination antiarrhythmic drug therapy for ventricular tachyarrhythmias. PACE
1986;9:565-576
64. Breithardt G, Seipel L, Abendroth RR: Comparison of the antiarrhythmic efficacy of disopyramide and mexiletine against stimulus-induced ventricular tachycardia. J Cardiovasc Pharmacol 1981;
3:1026-1037
65. Furlanello F, Bettini R, Bertoldi A, Vergara G, Visona L, Durante
GB, Inama G, Frisanco L, Antolini R, Zanuttini D: Arrhythmia
patterns in athletes with arrhythmogenic right ventricular dysplasia. Eur Heart J 1989;10(suppl D):16-19
66. Lascault G, Laplaud 0, Frank R, Tonet J, Fontaine G, Grosgogeat
Y: Ventricular tachycardia features in right ventricular dysplasia
(RVD). Circulation 1988;78(suppl II):II-300
67. Pietras RJ, Lam W, Bauernfeind R, Sheikh A, Palieo E, Strasberg
B, Swiryn S, Rosen KM: Chronic recurrent right ventricular tachycardia in patients without ischemic heart disease: Clinical, hemodynamic and angiographic findings. Am Heart J 1983;105:357-366
68. Wilber DJ, Blakeman BM, Pifarre R, Scanlon PJ: Catecholamine
sensitive right ventricular outflow tract tachycardia: Intraoperative
mapping and ablation of a free wall focus. PACE 1989;12:
1851-1856
Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular
disease. Results in patients with inducible and noninducible ventricular tachycardia.
T Wichter, M Borggrefe, W Haverkamp, X Chen and G Breithardt
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Circulation. 1992;86:29-37
doi: 10.1161/01.CIR.86.1.29
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1992 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://circ.ahajournals.org/content/86/1/29
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally
published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further
information about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/