Download Calcium channel blockers and beta-blockers versus beta

Calcium channel blockers and beta-blockers versus
beta-blockers alone for preventing exercise-induced arrhythmias
in catecholaminergic polymorphic ventricular tachycardia
Rafael Rosso, MD,* Jonathan M. Kalman, MD,‡ Ori Rogowski, MD,* Shmuel Diamant, MD,†
Amir Birger, MD,† Simon Biner, MD,* Bernard Belhassen, MD,* Sami Viskin, MD*
From the *Department of Cardiology and †Pediatrics, Tel Aviv Sourasky Medical Center, Sackler School of Medicine,
Tel Aviv University, Israel, and the ‡Department of Cardiology, University Royal Melbourne Hospital and University of
Melbourne, Melbourne, Australia.
BACKGROUND The mainstay of therapy for catecholaminergic polymorphic ventricular tachycardia (CPVT) is maximal doses of ␤-blockers. However, although ␤-blockers prevent exercise-induced ventricular tachycardia (VT), most patients continue to have ventricular
ectopy during exercise, and some studies report high mortality rates
despite ␤-blockade.
OBJECTIVE The purpose of this study was to investigate whether
combining a calcium channel blocker with ␤-blockers would prevent
ventricular arrhythmias during exercise better than ␤-blockers alone
since the mutations causing CPVT lead to intracellular calcium overload.
METHODS Five patients with CPVT and one with polymorphic VT
(PVT) and hypertrophic cardiomyopathy who had exercise-induced
ventricular ectopy despite ␤-blocker therapy were studied. Symptomlimited exercise was first performed during maximal ␤-blocker therapy
and repeated after addition of oral verapamil.
RESULTS When comparing exercise during ␤-blockers with exercise
during ␤-blockers ⫹ verapamil, exercise-induced arrhythmias were
reduced: (1) Three patients had nonsustained VT on ␤-blockers, and
Introduction
Catecholaminergic polymorphic ventricular tachycardia
(CPVT) is a congenital disease characterized by exercise- or
stress-induced syncope or cardiac arrest due to ventricular
tachyarrhythmias in the absence of QT prolongation or
organic heart disease.1 The hallmark of this disease is the
reproducible provocation of polymorphic ventricular arrhythmias during exercise.2 Typically, patients with CPVT
have a normal electrocardiogram (ECG) at rest; however, as
the intensity of exercise increases, they develop atrial tachycardia or fibrillation, unifocal and then multifocal ventricular extrasystoles, a diagnostic bidirectional ventricular
tachycardia (VT), and polymorphic VT.1–3 Deterioration of
Address reprint requests and correspondence: Sami Viskin, M.D., Department of Cardiology, Tel Aviv Medical Center, Weizman 6, Tel Aviv
64239, Israel. E-mail address: [email protected]. (Received
March 6, 2007; accepted May 19, 2007.)
none of them had VT on combination therapy. (2) The number of
ventricular ectopics during the whole exercise test went down from
78 ⫾ 59 beats to 6 ⫾ 8 beats; the ratio of ventricular ectopic to sinus
beats during the 10-second period recorded at the time of the worst
ventricular arrhythmia went down from 0.9 ⫾ 0.4 to 0.2 ⫾ 0.2. One
patient with recurrent spontaneous VT leading to multiple shocks
from her implanted cardioverter-defibrillator (ICD) despite maximal
␤-blocker therapy (14 ICD shocks over 6 months while on ␤-blockers)
has remained free of arrhythmias (for 7 months) since the addition of
verapamil therapy.
CONCLUSIONS This preliminary evidence suggests that ␤-blockers
and calcium blockers could be better than ␤-blockers alone for preventing exercise-induced arrhythmias in CPVT.
KEYWORDS Catecholaminergic polymorphic ventricular tachycardia; ␤-Adrenergic blockers; Calcium channel blockers; Exercise;
Ryanodine
(Heart Rhythm 2007;4:1149 –1154) © 2007 Heart Rhythm Society.
All rights reserved.
exercise-induced polymorphic VT to ventricular fibrillation
(VF) has been documented in CPVT.4
Ever since the causal association between stress and
arrhythmic symptoms of CPVT was recognized,2
␤-blockers have been the mainstay of therapy.1– 6 Moreover, since polymorphic VT is reproducibly induced with
exercise in the majority of patients with CPVT,2,5–7 it is
common practice to use repeated exercise testing to evaluate the efficacy of ␤-blocker therapy.1– 6 Indeed,
␤-blockers are very effective for preventing exerciseinduced sustained polymorphic VT.1– 6 However, the majority of patients with CPVT continue to have different
degrees of ventricular ectopy during exercise despite
maximally tolerated dosages of ␤-blockers.5,8 Moreover,
some studies report high mortality rates4 and a high
incidence of recurrent polymorphic VT7 despite
␤-blocker therapy. Thus, additional forms of therapy are
needed for this potentially lethal disease.3 Since the ma-
1547-5271/$ -see front matter © 2007 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2007.05.017
1150
Table 1
Heart Rhythm, Vol 4, No 9, September 2007
Patient characteristics
Patient
Gender
Age at onset of symptoms
(present age), years
Weight, kg
Symptoms before therapy
␤-blocker dose, mg/day
1
Female
12 (28)
90
CA, S(⫹⫹)
Metoprolol 400
2*
Male
6 (8)
50
S(⫹)
Propranolol 160
3†
Male
12 (13)
43
S
Bisoprolol 5
4
Female
11 (12)
26
S‡
Bisoprolol 2.5
5§
Female
10 (32)
CA, S(⫹)‡
Atenolol 200
6
Female
69 (69)
—
Atenolol 150
58
Combined therapy,
mg/day
Propranolol 360 ⫹
verapamil 240
Propranolol 160 ⫹
verapamil 120
Bisoprolol 5 ⫹
verapamil 120
Bisoprolol 2.5 ⫹
verapamil 120
Atenolol 200 ⫹
verapamil 240
Atenolol 150 ⫹
verapamil 240
CA ⫽ cardiac arrest; S ⫽ syncope (invariably malignant and with seizures). *Patient 2 is the son of patient 1. †Patients 3 and 4 are brothers. ‡Patients
4 and 5 presented with near drowning. §Patient 5 is the only one with implanted ICD. Patient 6 has hypertrophic cardiomyopathy.
jority of mutations causing CPVT lead to intracellular
calcium overload, we theorized that adding calcium channel blockers to a therapeutic regimen of ␤-blockers
would prevent ventricular arrhythmias better than
␤-blockers alone.
Methods
Patients
Seven patients with CPVT were studied. All the CPVT patients have a history (or familial history) of syncope and/or
cardiac arrest, and all of them have documented exercise-induced
Figure 1
Patient 2 presented with recurrent malignant syncope during physical (running) or emotional (fright) stress. His mother (patient 1) has CPVT and has
been reported elsewhere.1 A: The baseline ECG shows a normal “juvenile pattern” with tall R waves and inverted T waves in the right precordial leads. The QT
is normal (QTc ⫽ 430 ms). B: During exercise in the absence of treatment, he develops bidirectional VT (see little square marked * in V5) and rapid polymorphic
VT (reaching ventricular rates of 270/min). The boy was asymptomatic during this test. C: A repeated exercise test during ␤-blocker therapy (propranolol 3
mg/kg/day, total 160 mg/day) shows marked improvement: rapid VT is no longer present, but ventricular bigeminy and short bursts of nonsustained VT (**) are
still provoked by exercise. During maximal exercise while receiving ␤-blocker and calcium-blocker therapy (verapamil 2.5 mg/kg, 120 mg/day), there are motion
artifacts caused by running, but there are no ventricular arrhythmias.
Rosso et al
Calcium Channel Blockers and Beta-Blockers in CPVT
1151
Figure 2
Asymptomatic 69-year-old female (patient 5) with reproducible provocation of exercise-induced polymorphic VT. A: The baseline ECG is strictly
normal; the QTc is 410 ms. B: During exercise in the absence of drugs she develops incessant nonsustained polymorphic VT with only isolated sinus complexes.
C: During therapy with atenolol 150 mg/day, she no longer has VT but has ventricular couplets, and ventricular triplets (*). During therapy with atenolol 150 mg
⫹ verapamil 240 mg/day, she has only isolated ventricular ectopy during maximal exercise.
polymorphic and/or bidirectional VT. Two of these patients had
total suppression of exercise-induced ventricular arrhythmias with
␤-blockers and were therefore not included in this study. The
remaining five patients, who had reproducible provocation of
exercise-induced ventricular ectopy despite maximally tolerated
doses of ␤-blocker therapy, were included (Table 1). None of the
CPVT patients have been genotyped. However, their clinical history and documented arrhythmias are diagnostic of CPVT (Figure
1A).1,3 We also included a 69-year-old female with exerciseinduced atrial and ventricular arrhythmias. The characteristics of
the last patient are less typical for CPVT because she is elderly and
asymptomatic and because she has left ventricular hypertrophy
consistent with hypertrophic cardiomyopathy. She was nevertheless included because she has reproducible provocation of repetitive nonsustained polymorphic VT on submaximal exercise (Figure 2A). It should be noted that even though CPVT was initially
considered a disease of children,2 CPVT presenting in adulthood
has recently been described.7 Also, although CPVT is considered
a channelopathy causing electrical but no morphologic abnormalities, in an animal model of CPVT, mice with calsequestrin 2
mutations developed hypertrophic cardiomyopathy as a late manifestation.9
Exercise testing
To establish the diagnosis of CPVT and confirm the reproducibility of exercise-induced arrhythmias, symptom-limited exercise tests were performed twice (10 minutes apart) in the
absence of therapy. Oral ␤-blockers were started and gradually
increased until side effects (fatigue) occurred. The doses were
then reduced to the maximally tolerated dosages, and a maximal exercise stress test was performed. To confirm the reproducibility of exercise-induced arrhythmias despite ␤-blockers,
a second exercise test was performed after 10 minutes of rest.
As mentioned above, only the six patients who had reproducible provocation of ventricular arrhythmias with exercise despite adequate ␤-blocker therapy were included in this study.
These six patients then received oral verapamil (at daily doses
of 2–3 mg/kg/day for children and 240 mg/day for adults) in
addition to their permanent ␤-blocker regimen, and a symptom-limited exercise was repeated 1–2 weeks later. To test for
the reproducibility of efficacy of this combination therapy, a
similar test was performed after 10 minutes of rest. One patient
(patient 5) with typical CPVT refused to repeat the exercise
stress test after initiation of the combination therapy because of
intense fear of exercise-induced arrhythmias. She was never-
1152
Heart Rhythm, Vol 4, No 9, September 2007
Table 2
Exercise testing of patients with CPVT*
Variable
␤-blockers
Sinus rate at baseline, bpm
Sinus rate at the onset of ventricular arrhythmias, bpm
Sinus rate at the time of the worst arrhythmias, bpm
Sinus rate at maximal exercise, bpm
Maximal treadmill speed,† km/hour
Maximal treadmill grade†
Maximal number of ventricular ectopic beats
Maximal number of ventricular ectopic beats during the worst
10 seconds period
Maximal ratio of ventricular ectopic to sinus beats during the worst
10-second period‡
64
117
135
150
6.9
10.8°
78
11.0
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
9
19
29
22
1.3
6.1°
59
3.1
0.9 ⫾ 0.4
␤-blockers ⫹
calcium blockers
66
115
123
136
7.5
9.1°
6
2.6
⫾
⫾
⫾
⫾
⫾
⫾
⫾
⫾
8
15
11
19
1.3
5.9°
8
2.7
0.2 ⫾ 0.2
P
.89
.72
.29
.07
.72
.29
.04
.04
.04
*Data for five patients. All exercise tests were symptom limited (the only reason for discontinuation was patient exhaustion). †Maximal treadmill speed and
grade sustained for at least 1 minute. ‡To obtain this value, the number of ventricular ectopics was divided by the number of sinus beats recorded during a 10-second
period at the time of the worst ventricular arrhythmia.
theless included in this report because the addition of verapamil to her ␤-blocker regimen led to a dramatic reduction in
appropriate shocks delivered by her implantable cardioverterdefibrillator (ICD; see below).
ered statistically significant. The SPSS statistical package was
used to perform all statistical evaluation (SSPS Inc., Chicago).
Results
Patient characteristics
Statistics
We compared the sinus rate at the onset of ventricular arrhythmia, at the time of the worst arrhythmia and at maximal
exercise, first during ␤-blocker therapy and then during combined ␤- and calcium-blocker therapy. The measured outcome
was the degree of exercise-induced arrhythmias, expressed as
(1) the presence or absence of atrial fibrillation or nonsustained
VT; (2) the total number of ventricular ectopic beats during the
whole exercise test; and (3) the number of ventricular ectopic
beats during the worst 10-second period of the exercise test.
Data are presented as number ⫾ standard deviation for all
continuous variables and as number and percent of dichotomous variables. Because of the very small number of individuals, all statistical analyses were nonparametric. For continuous variables, the comparison was done using the paired
Wilcoxon signed ranks test, while for dichotomous variables
the McNemar test was used. P ⬍.05 (two tailed) was consid-
The six patients included in the study are from four different
families (Table 1). Before the onset of ␤-blocker therapy, one
of them had cardiac arrest, two had near drowning,10 and two
had recurrent malignant syncope with seizures. Three of these
patients also experienced arrhythmic symptoms while receiving ␤-blocker therapy (recurrent syncope in two patients and
multiple ICD shocks for polymorphic VT in one patient). The
other three patients were rendered asymptomatic by ␤-blockers
but had persistent and reproducible exercise-induced ventricular arrhythmias despite ␤-blockade.
Effects of combined (calcium- and ␤-blocker)
therapy on exercise testing
The addition of verapamil to the ␤-blocker regimen did not
significantly affect the sinus rate recorded at baseline or at the
onset of ventricular arrhythmias (Table 2). However, all patients had fewer exercise-induced ventricular arrhythmias dur-
A
B
Number of ectopic beats
Ratio of ectopic to sinus beats
for each patient.
C
Number of patients
With NSVT
for each patient.
1.6
180
5
80
0.8
4
60
0.6
3
40
0.4
2
20
0.2
1
0
I
II
ß-blockers
I
II
ß-blockers
+ Ca blockers
0
I
II
ß-blockers
I
II
ß-blockers
+ Ca blockers
0
ß-blockers ß-blockers
+ Ca blockers
Figure 3 A and B: The ventricular
arrhythmias developed by each patient
during four exercise tests: one pair of exercise tests on ␤-blockers and one pair
during combination therapy with
␤-blockers and calcium blockers. A: Total number of ventricular ectopic beats
recorded during the whole test. B: The
number of ventricular ectopic beats divided by the number of sinus beats during
a 10-second period recorded at the time of
the worst ventricular arrhythmia recorded
during each exercise test. C: The number
of patients with at least one episode of
nonsustained VT.
Rosso et al
Calcium Channel Blockers and Beta-Blockers in CPVT
ing calcium- and ␤-blocker therapy than during ␤-blocker
therapy alone (Figures 1–3). Figure 3A shows the total number
of ectopic beats recorded for each patient during four exercise
tests (the first two tests on ␤-blockers and the second pair
during therapy with ␤-blockers and verapamil). All four tests
were symptom limited, and the only reason for discontinuation
was patient exhaustion. The second test on ␤-blockers alone
already shows fewer ectopic beats in comparison with the first
test (Figure 3A), which reflects the fact that the rest period
between the first two tests was brief, resulting in earlier exhaustion during the second test on ␤-blockers. Nevertheless, a
further unequivocal and obvious decrement in the amount of
ectopy occurred after 1–2 weeks of therapy with ␤-blockers
plus calcium blockers. Importantly, the maximal treadmill
speed and treadmill grade (reflecting the maximal exercise
challenge) during exercise tests number 1 and 3 (the first
exercise test performed on ␤-blockers and the first exercise test
on combination therapy, respectively) were similar (Table 2).
Figure 3B shows the ratio of ectopic beats to sinus beats during
a 10-second period at the time of the worst ventricular arrhythmia recorded during each of the four tests. Again, the improvement in the degree of ventricular arrhythmias achieved after
the addition of verapamil is unequivocal for each patient.
Finally, exercise-induced nonsustained VT was recorded during ␤-blocker therapy in four patients but never during combined therapy. Exercise-induced atrial tachycardia/fibrillation
occurred in the absence of therapy in two patients, during
␤-blockers in one, and during combined therapy in none.
Effects of combined (calcium- and ␤-blocker)
therapy on clinical outcome
The three patients who were asymptomatic on ␤-blocker therapy
have remained free of clinical arrhythmias while on combined
therapy for 13 ⫾ 8 additional months. Two patients who had
recurrent syncope while on ␤-blockers had a single episode of
syncope while receiving combination therapy. This includes patient 1 and her 8-year-old son, who had a seizure episode triggered
by panic. Of note, the child had a totally negative exercise test on
verapamil and ␤-blockers 2 months before the last syncope and
once again shortly thereafter. Finally, one patient had 14 appropriate ICD shocks for spontaneous rapid polymorphic VT during
atrial fibrillation during a 6-month period on ␤-blocker therapy.
The same patient has remained completely free of arrhythmias
since the addition of verapamil to her ␤-blocker therapy 7 months
ago. No patient died.
Side effects
Four patients intermittently complained of fatigue while on
␤-blocker therapy, but this symptom did not worsen after the
addition of verapamil. One mother and her son suffer from
chronic photophobia (requiring constant use of sunglasses)
ever since verapamil therapy was started.
Discussion
CPVT is a rare disease, and spontaneous arrhythmias occur sporadically yet may be fatal.3 Therefore, demonstrating clinical efficacy for any drug therapy is difficult. On the other hand, most
1153
patients with CPVT (and all the patients ultimately included in this
study) have easy and reproducible provocation of arrhythmias
with exercise. For the present study, we took advantage of the easy
provocation of arrhythmias in CPVT and showed that adding a
calcium channel blocker to a ␤-blocker regimen further reduces
the severity of exercise-induced arrhythmias.
Main findings
Clinical efficacy of the verapamil plus ␤-blocker combination
was clearly demonstrated for one patient, who had a dramatic
reduction in the number of spontaneous VT events triggering
ICD shocks. For the other patients, prevention of exerciseinduced VT and/or obvious reduction of exercise-induced ectopy were demonstrated. Arrhythmia suppression by the verapamil ⫹ ␤-blocker combination occurred without affecting the
sinus rate recorded at the time of ventricular arrhythmias. This
suggests that verapamil reduced the amplitude of delayed depolarizations (DADs) below the amplitude threshold required
for triggering ventricular arrhythmias (see below).
Rationale for combining calcium and ␤-blockers
Normally, small calcium currents that enter the cardiomyocyte
through L-type calcium channels in the cell membrane trigger
a larger flow of calcium current (needed for the excitationcontraction coupling in the heart) from intracellular deposits
(the sarcoplasmic reticulum). During stress, stimulation of
␤-adrenergic receptors results in cyclic-AMP-dependent phosphorylation of the ryanodine channels, opening these channels
to boost the flow of calcium from the sarcoplasmic reticulum.
In CPVT, mutations in the genes encoding for the ryanodine
channel6,11 (the channel controlling the passage of calcium
current from the sarcoplasmic reticulum) or for the calciumbuffering protein calsequestrin12 (the calcium-binding protein
that controls its release through the ryanodine channel) lead to
excessive release of calcium currents. This excess of positiveion calcium current depolarizes the myocyte at the end of the
action potential, creating DADs. As beautifully explained by
other investigators,13–15 calcium-mediated DADs reaching
threshold potential trigger the arrhythmias of CPVT. Thus,
patients with CPVT need ␤-blockers to prevent the adrenergic
augmentation of calcium flow through the genetically defective ryanodine channel. Verapamil could further prevent arrhythmias by blocking the L-type calcium channels in the cell
membrane, reducing the amount of intracellular calcium that
incites the calcium-dependent calcium release from the defective sarcoplasmic reticulum. Verapamil could further reduce
the passage of calcium through the ryanodine channel either
through a direct blocking action16 or by further reducing cyclic
AMP.17 In addition, the negative dromotropic effects of verapamil may be important because patients with CPVT often
have catecholaminergic atrial fibrillation. By further decreasing the ventricular rate during atrial fibrillation, verapamil may
prevent rate-dependent triggered (DAD mediated) ventricular
arrhythmias. Finally, in animal models of CPVT,15 DADs
generated in the epicardium are more likely to trigger extrasystoles. This could be related to a larger influx of calcium
through L-type calcium channels in epicardial cells.15 Block-
1154
ing epicardial DADs with verapamil is particularly important
because extrasystoles originating in the epicardium increase
the dispersion of repolarization and facilitate the degeneration
of bidirectional VT to VF.15 Thus, at least in theory, patients
with CPVT should receive both ␤-blockers and calcium blockers to prevent the onset of VT (␤-blockers) and its degeneration to VF (calcium blockers).
Previous studies
A single case of bidirectional VT due to Andersen’s syndrome
(a rare disease caused by malfunction of the inward-rectifier
potassium channel) that responded to therapy with verapamil
was reported by Kannankeril et al.18 More recently, Swan et
al19 demonstrated that a single dose of intravenous verapamil
to six patients with CPVT, including five patients receiving
oral ␤-blocker therapy, significantly reduced the amount of
exercise-induced VT in an acute study.
Limitations
Because of the small number of patients and the limited follow-up,
our results should be viewed as preliminary. Also, the fact that one
patient had syncope during panic, while receiving therapy that was
protective during exercise, emphasizes that emotional and physical stress cannot always be equated. Thus, negative exercise tests
do not invariably imply an event-free prognosis.
Clinical implications
CPVT is a malignant disease. Without therapy, 30%–50% of
patients die suddenly at a young age.3 Even with ␤-blocker therapy, unacceptably high mortality rates—as high as 19%—have
been reported.4 Therefore, some investigators have proposed ICD
implantation for high-risk patients.3,7 However, ICD implantation
in CPVT has drawbacks: (1) CPVT mostly affects children, and
ICD implantation in children incurs significant morbidity20 and
complications.21 (2) Polymorphic VT will not terminate with ICD
shocks. Programming the ICD with long detection times so
shocks are delivered after this VT (triggered activity) degenerates
to VF (reentry) is problematic.22 (3) ICD shocks are painful and
frightening, and the resulting catecholamine surge would be extremely proarrhythmic in CPVT. Fatal arrhythmic storms triggered by ICD shocks may occur,22 and frequent shocks23 may be
emotionally devastating for children. Therefore, therapy aimed at
preventing the onset of VT should be optimized. ␤-blocker therapy is mandatory, but it is not always effective.4,7 Verapamil (in
addition to ␤-blockers) may further reduce the amount of exercise-induced arrhythmias and should be strongly considered for
patients with persistent symptoms. We do recognize that the data
presented here are very limited and should be viewed as preliminary. Nevertheless, considering the theoretical rationale for this
therapy and recognizing that standard therapy is far from ideal, we
would argue that prescribing ␤- and calcium blockers to all patients with CPVT who have exercise-induced arrhythmias despite
adequate ␤-blockade is a reasonable approach.
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