Download A Clinical Approach to Common Cardiovascular Disorders When

A Clinical Approach to Common Cardiovascular
Disorders When There Is a Family History
A Clinical Approach to Inherited Arrhythmias
Marina Cerrone, MD; Samori Cummings, MD; Tarek Alansari, MD; Silvia G. Priori, MD, PhD
I
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however, roughly 10% to 15% of patients experience symptoms at rest or during the night.5 The mean age of onset of
symptoms is 12 years, and earlier onset usually is associated
with a more severe form of the disease.4
The diagnosis of LQTS is based on the ECG and the
measurement of the heart rate corrected QT interval (QTc).
Cut-off values have been established based on the use of
Bazett formula. Normally, QTc should not exceed >440 ms
in males and >460 ms in postpuberal females. Additionally,
patients affected by congenital LQTS show frequent abnormalities in the T wave morphology (Figure 1), ie, diphasic T waves, notches, low amplitude, or very slow onset.6
Macroscopic T wave alternans is rare, but it correlates with
poor prognosis. The evaluation of QT interval duration during the diagnostic process requires a trained eye and the
availability of several examples at different heart rates. To
avoid over- or underestimation, we suggest measuring the
QT interval and choosing traces in which the RR interval is
constant for at least 10 to 20 beats. Considering the limitation of Bazett formula, that it is nonlinear at fast or slow
heart rates, we prefer to exclude from the evaluation traces
with heart rate >100 bpm or <50 bpm.
The QT interval is the most important indicator of risk.
Patients who present with QTc >500 ms repetitively are considered at high risk for arrhythmias and SCD.3,4
The syndrome can present with incomplete penetrance,
and 10% to 35% of genetically affected patients show a normal QTc interval despite being genetically affected by the
disease7,8 (Figure 2). The identification of these individuals
within a family often can be established only through genetic
testing; the clinical value of identifying silent carriers is
based on the evidence that these patients may experience
arrhythmic events. In our series of patients, approximately
10% of silent carriers of a disease-causing mutation experienced symptoms mainly when they were treated with QT
prolonging drugs.3
The first therapeutic approach for all patients is β-blocker
therapy. Using the evidence that 10% of silent gene carriers are at risk of cardiac events in spite of presenting with
normal QT intervals, and LQTS patients remain at risk of
experiencing symptoms after age 40,9 we initiate prophylactic
n the past decade, the discovery that cases of ventricular arrhythmias and sudden cardiac death (SCD)
in young individuals potentially could be caused by an
unrecognized genetic substrate has defined a new subset
of cardiac conditions: inherited arrhythmogenic diseases
(IADs).1 Although rare in clinical practice, these diseases
are more common than previously thought. They represent
a challenge for the arrhythmia specialist in terms of diagnosis and clinical management. The correct diagnosis of
IADs, as well as the use and interpretation of the results
of genetic testing, are not straightforward and require a
specific expertise such as that provided by specialized and
dedicated centers. Here we will review the general issues
arising from the correct interpretation of genetic testing
and its indications. We also will focus on the clinical management and use of genetic information in different inherited arrhythmias.
Cardiac Channelopathies
The term “channelopathies” defines a group of inherited
arrhythmic syndromes caused by mutations on genes encoding for ion channel proteins and proteins that regulate ion
channels.1 These mutations disrupt the balance of currents
in the cardiac action potential, favoring the onset of lifethreatening arrhythmias in the absence of structural heart
defects.
The Long QT Syndrome
The long QT syndrome (LQTS) is a heritable channelopathy
characterized by an exceedingly prolonged cardiac repolarization that may trigger ventricular arrhythmias and SCD.2 LQTS
is one of the first channelopathies in which clinical and genetic
features have been discovered, and a large series of patients
have been collected and followed over the years.2–4 Thanks to
these studies, LQTS management takes into account a patient’s
genetic background and has become a paradigm for the use of
genetic information applied to the clinical practice.3,4
Clinical Characteristics and Diagnosis
Long QT syndrome can manifest with syncope and cardiac
arrest. These commonly are triggered by adrenergic stress;
From the Cardiovascular Genetics, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY (M.C., S.C., T.A.,
S.G.P.); Division of Cardiology and Molecular Cardiology, Fondazione S. Maugeri IRCCS, Pavia, Italy (S.G.P.); and Department of Cardiology, Universita’
degli Studi di Pavia, Pavia, Italy (S.G.P.).
Correspondence to Silvia G. Priori, MD, PhD, Division of Cardiology and Molecular Cardiology, Fondazione S. Maugeri IRCCS, Via S. Maugeri
10/10A, 27100 Pavia, Italy, E-mail [email protected].
(Circ Cardiovasc Genet. 2012;5:581-590.)
© 2012 American Heart Association, Inc.
Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org
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DOI: 10.1161/CIRCGENETICS.110.959429.
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Figure 1. Left: ECG of a long QT syndrome patient. Right: ECG of a short QT syndrome patient. Note in both cases the peculiar morphology of the T wave.
β-blocker therapy at the time of diagnosis. No data are available to establish if there are differences in the efficacy of
different -blockers, nor are systematic dose-response curves
available. It is our practice to preferentially use nadolol (with
a dose of 1 mg/Kg/d) over other β-blockers given its long
half-life and efficacy. In the presence of recurrent symptoms
while on therapy or in high-risk patients, an implantable cardioverter-defibrillator (ICD) should be considered.4
Genetic Substrate
Figure 2. Incomplete penetrance of LQTS. Genetically affected
patients can show normal corrected QT interval duration. Data
from Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E,
Nastoli J, et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in
clinical practice. JAMA. 2005;294:2975–2980.
Long QT syndrome presents with 2 different modes of transmission.1 The autosomal dominant form (Romano Ward syndrome) is the most common. The rare autosomal recessive
form (Jervell-Lange-Nielsen syndrome) is associated with
concomitant neurosensorial deafness. Only 2 genes (KCNQ1
and KCNE1) have been linked to this form and should be suspected if consanguinity is present in the family in addition to
deafness.10
The list of LQTS genes causing the autosomal dominant variant is expanding constantly, and currently totals 13
genes.1,10,11 All encode for ion channel proteins or for proteins
such as chaperons and modulators that regulate ion channels.
Therefore, the final common consequence of LQTS mutations
is the disruption of 1 or more ionic currents of the cardiac
action potential, ultimately resulting in abnormally prolonged repolarization. Despite the remarkable heterogeneity
Cerrone et al Clinics of Inherited Arrhythmias 583
Table 1. Yield of Genetic Test in Inherited Channelopathies
Disease
Yield of Genetic Test
LQTS
75 (80)%
Brugada syndrome
20 (30)%
CPVT
60 (70)%
SQTS
unknown
The number in parentheses includes all known genes tested in commercial
panels. Data modified from Ackerman MJ, Priori SG, Willems S, Berul C,
Brugada R, Calkins H, et al. HRS/EHRA expert consensus statement on the state
of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm.
2011;8:1308–1339.
LQTS indicates Long QT Syndrome; CPVT, Catecholaminergic Polymorphic
Ventricular Tachycardia; and SQTS: Short QT Syndrome
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of LQTS, the 3 forms that were first described (LQT1,
LQT2, and LQT3) account for >90% of genotyped patients
(Table 1).12 These 3 forms represent the variants from which
it has been possible to perform genotype-phenotype correlations and genotype-based risk stratifications studies.3,4,10,11
Mutations on the KCNQ1 gene encoding for the α-subunit
of the channel for the IKs repolarizing current cause LQT1.10
The LQT2 form is linked to mutations on the gene KCNH2
for the α-subunit of the channel for the IKr repolarizing current.10 In both cases, mutations cause a loss of function in
the protein, leading to reduced repolarizing potassium current. The LQT3 variant is caused by mutations on the SCN5A
gene encoding for the alpha subunit of the cardiac sodium
channel.10 These mutations increase the late INa depolarizing
current, thus ultimately resulting in prolonged action potential duration.
Genotype-Phenotype Correlations
Initial observations noted that T waves in LQTS patients
showed gene-specific differences.6 This prompted investigators to study if additional specific differences could be
identified among LQT1, LQT2, and LQT3, and applied to
the clinical practice. It was discovered initially that triggers
for cardiac events are different among the 3 forms.5 LQT1
patients have the highest incidence of arrhythmic events
during exercise. LQT2 patients are more sensitive to strong
emotions, particularly to startling noises. LQT3 patients experience most of their events at rest or during sleep. However,
it is important to keep in mind that overlap may exist and
that these data are only 1 of the parameters to be taken into
account in the patients’ evaluation. The evaluation of genotype/phenotype correlations in our large Italian population
highlighted that genotype is an independent risk predictor
(Figure 3), and also may influence the response to treatment with β-blockers.3,4 The 2 studies showed that, although
LQT1 patients respond very well to β-blockers (Figure 4), in
patients with LQT2 and LQT3 arrhythmic events recur more
frequently despite β-blockers. The influence of the genetic
substrate on the clinical course of LQTS also has been
availed by the American College of Cardiology, American
Heart Association, and European Society of Cardiology 2006
Figure 3. Event-free survival in long QT syndrome according
to the genotype in the absence of β-blockers. Data from Priori
SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M,
et al. Risk stratification in the long-QT syndrome. N Engl J Med.
2003;348:1866–1874.
Guidelines for the prevention of SCD.13 That sparked the
consideration of ICD implantation as primary prevention of
cardiac arrest for LQT2 or LQT3 patients with QTc >500 ms.
It is, however, our advice that physicians use a multiparametric and individualized approach in the assessment of
their patients and avoid using genotype as the only indicator of risk. Accordingly, a patient with LQT1 and a very
prolonged QT interval is most likely at higher risk of lifethreatening arrhythmias than an individual with LQT3 and
a borderline QTc.
Novel therapeutic approaches targeting the genetic defect
also have been proposed. Considering the incomplete protection afforded by β-blockers in LQT3 and the reduced influence of adrenergic stress as an arrhythmic trigger, sodium
channel blockers, such as mexiletine or flecainide, were suggested as potential therapy.14,15 Initially, the use of sodium
channel blockers in all LQT3 patients was considered of
potential benefit, though it later became evident that not all
LQT3 patients respond to mexiletine with QTc shortening. In
vitro studies demonstrated that specific mutations have different responses to the drug, suggesting that in vitro testing
of the response to sodium channel blockers might be helpful to guide management of LQT3 patients.16,17 These studies
in cell systems are among the first to demonstrate the role
bench studies can have in the clinical assessment of inherited
arrhythmias toward tailoring appropriate treatment to each
individual.
It is worth highlighting that given the small number of
LQT3 patients at present time there is no evidence that therapy with sodium channel blockers influences outcome in this
group.
Indications and Use of Genetic Test in Long
QT Syndrome
Genetic testing is especially useful in LQTS in the presence
of a clear clinical phenotype. If the patient shows a prolonged
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Figure 4. Different event-free survival in β-blocker therapy in catecholaminergic polymorphic ventricular tachycardia (CPVT) and in long
QT 1, showing the high rate of recurrences in CPVT. Data are derived from the authors’ database TRIAD (Transatlantic Registry of
Inherited Arrhythmogenic Diseases).
QTc, the identification of the specific genotype can orient
treatment and risk stratification. As an example, the effectiveness of β-blockers in controlling recurrent arrhythmic episodes is higher in LQT1 patients (Figure 4), whereas a QTc
>500 ms, a history of symptoms, and a LQT2 or LQT3 genotype may prompt a more aggressive approach.4
Due to the incomplete penetrance of LQTS, the use of
genetic testing to diagnose silent gene-carriers among family members is highly recommended. In the same perspective,
genetic test also can identify those family members who are
not carriers of the disease, providing a conclusive diagnosis
and limiting the need of periodic clinical evaluations and prophylactic therapy.
More blurred are the indications for genetic testing in borderline cases, where the yield of the test is low and the absence
of a mutation is not sufficient per se to exclude the diagnosis.
Additionally, the yield of the test in diagnosing the newer and
rarer LQTS variants, beyond LQT1, LQT2, and LQT3, is still
low, and the interpretation of the results remains challenging
(Table 1).
An emerging issue is the correct interpretation of the effect
of novel unreported variants and their potential to cause the
phenotype. In this perspective, data from the literature, functional studies, and cosegregation of genotype/phenotype
in large pedigrees when available are all elements that one
should consider when assessing the significance of a genetic
test.
The Brugada Syndrome
In the early 1990s, Pedro and Josep Brugada described a new
disease characterized by familial transmission, structurally
normal heart, and high incidence of ventricular arrhythmias
and SCD, which now bears their name.18 The Brugada syndrome (BrS) is an IAD characterized by a peculiar surface
ECG and arrhythmias mostly occurring at rest, during sleep,
in the presence of fever, and after large meals.19,20 As described
below, it is a condition that continues to puzzle electrophysiologists and cardio-geneticists because of its challenging diagnosis and treatment.
Clinical Characteristics and Diagnosis
The BrS is characterized by arrhythmias mostly occurring
at rest or during sleep. Patients present with ST-segment
elevation in the right precordial leads, often in the presence
of right bundle-branch block on the surface ECG, in the
absence of acute cardiac ischemia.18 The ST segment morphology, considered diagnostic, is indicated as type 1 and
presents a “coved” aspect21 (Figure 5). However, the patterns
indicated as type 2 (saddle-back, elevation >2.5 mm) or type
3 (coved or saddle-back with ST elevation <2.5 mm) should
be considered suspect for the disease21 and prompt medical
attention.
One of the challenges in recognizing BrS is the transitory
nature of the ECG pattern as it is often intermittent and difficult to detect in a single ECG tracing (Figure 5). For that
reason, to diagnose affected patients, 12-lead ECG Holters
should be performed, allowing for prolonged monitoring of
the right precordial leads.
A diagnostic pattern may be unmasked by the infusion
of sodium channel blockers flecainide, procainamide, and
ajmaline.21,22 Different reports suggested that ajmaline and
flecainide might have increased sensitivity in unmasking
Brugada syndrome if compared with procainamide, which is
the only injectable sodium channel blocker available in the
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Figure 5. ECG-Holter of 1 patient affected by BrS, showing dynamic spontaneous changes in ST segment morphology, from type 3 (left),
to type 2 (middle), to type 1 (right,) occurring in the same day.
United States.22,23 To shed some light on this controversy, a
Food and Drug Administration approved evaluation aimed to
compare the diagnostic sensitivity of flecainide versus procainamide infusion is now ongoing in our center.
The type 1 pattern also may appear after abundant meals or
during fever,19 both of which have been indicated as potential
arrhythmic triggers. Supraventricular arrhythmias and atrial
fibrillation are common also.
The disease has autosomal dominant transmission.21 Despite
50% of the carriers of disease-causing mutations being female,
the vast majority of clinically affected patients are men, even
though it is still unknown how gender influences the manifestation of the disease.21
At variance with other IADs, symptoms tend to not manifest
in childhood, but they appear in the second to third decade,
and the arrhythmic risk then remains prevalent throughout
adulthood.21,24,25 Family history for cases of sudden death during sleep in young men may direct the diagnosis.
At present, no medical therapy has proven effective in
BrS, and the only treatment remains the ICD implant.18,21
Quinidine26 has been proposed as a potential therapy based on
preliminary encouraging data showing that it could reduce the
incidence of inducible ventricular tachycardia (VT)/ventricular fibrillation (VF) and ICD shocks in a subset of patients.26,27
Two clinical trials are now ongoing to test the effect of quinidine in BrS (NCT00789165 and NCT00927732). Awaiting
more conclusive evidence on the efficacy of quinidine, its
use is currently limited to ICD carriers experiencing repeated
appropriate device therapies.
Risk stratification is based on clinical parameters, and the
results of genetic testing at present time do not contribute
to the risk stratification process. The combined presence of
history of syncope with the presence of a spontaneous type
1 ECG is considered a marker of higher risk of SCD.25,28–30
Patients presenting with type 1 ECG only during pharmacological challenge are at lower risk to experience symptoms.
Neither a family history, nor the presence of a mutation in the
SCN5A gene have been shown to be risk indicators.25,28 The
predictive value of programmed electric stimulation has been
initially controversial25,30; however, several recent studies on
different series of patients agreed that it should not be used
as a parameter for risk stratification.25,28,29 The multicenter
prospective PRELUDE study, led by our group, recently has
confirmed the limited predictive value of programmed electric
stimulation in a large series of BrS patients, who all underwent the same stimulation protocol.31
Genetic Bases and Genotype-Phenotype Correlations
Only an exiguous number of BrS patients are genotyped
successfully. At present, 7 genes have been linked to the
disease, but altogether mutations are detected in only 25%
to 30% of patients (Table 1). Among the causative genes, 2
account for the majority of genotyped patients: SCN5A and
CACN1Ac.32,33
Mutations in the SCN5A gene coding for the cardiac sodium
channel also cause LQT3; thus, BrS and LQT3 are considered allelic diseases. Mutations linked to BrS have an opposite
electrophysiological effect as compared with those that cause
LQTS, and the Brugada phenotype is associated with “loss of
function” mutations in SCN5A. Other less represented genes
(SCN1B,34 SCN3B,35 and GPD1-L36) causing BrS participate in
the regulation of the sodium current, which has been shown to
play an important role in the pathophysiology of the disease.
The second most prevalent BrS gene is CACN1Ac,33 encoding
for the α-subunit of the cardiac calcium channel. Few cases
have been attributed also to mutations on the CACNB2 gene,33
encoding for the β-subunit of the same channel. In both cases,
mutations cause a loss of function that reduces the current.
Interestingly, loss of function mutations on these genes also
have been associated with another IAD, the short QT syndrome (SQTS). An intermediate phenotype sharing features
of both diseases has been reported as well.33
Genotype-phenotype correlation studies have provided limited results in the setting of BrS; therefore, as of today the
presence or absence of a mutation does not exert a prognostic
role nor contribute to the selection of treatment.25 The only
586 Circ Cardiovasc Genet October 2012
identified hallmark of the presence of a mutation on the
SCN5A gene is the higher incidence of conduction defects.37
Patients carrying mutations on the genes encoding for
the calcium channel subunits, on the contrary, tend to have
an abbreviated repolarization and usually present a QTc
<360 ms.33
Indications for Genetic Test
Genetic testing in BrS has the general indications to allow
diagnosing of affected family members and allowing prenatal
and reproductive counseling.
When the test is positive, extension to family members
is very useful as it allows identifying affected individuals
with a concealed clinical phenotype or to exclude not carriers. However, as in all IADs, a negative genetic test cannot
exclude the clinical diagnosis as it simply indicates that the
currently identified genes are not abnormal in a given patient.
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The Short QT Syndrome
One of the latest channelopathies to be reported is the SQTS,
characterized by an abnormally reduced cardiac repolarization
(Figure 1) that is associated with a high incidence of arrhythmias and SCD. Its description in 200038 introduced the concept that genetic alterations that affect cardiac repolarization,
either prolonging or reducing its duration, result in increased
arrhythmogenesis.
Clinical Characteristics and Diagnosis
The first SQTS family was described in 2000.38 As is common
in all new conditions, these first cases fall into the extreme
spectrum of clinical manifestations, and the QTc interval
found in the early families was often <300 ms. With the
increase of symptomatic patients diagnosed with short QT,
the cut-off for the definition of SQTS has been raised to values between 340 to 360 ms (Figure 1). Most patients show
tall, peaked, and narrow T waves, with an almost absent ST
segment and a relative long Tpeak-Tend interval.39 Analogous
to measuring the QT interval in LQTS, isolated recordings
are not sufficient for the diagnosis, and the QTc should be
measured in several instances, at different values of HR, and
mostly around 60 bpm.
Short QT syndrome patients have a high incidence of atrial
fibrillation and supraventricular arrhythmias, which also are
reported to occur in children.40 In several cases the first manifestation of symptoms is cardiac arrest, and a family history
of SCD is frequent.
The electrophysiological study can help in the diagnostic process because SQTS patients tend to present with very short atrial
and ventricular refractory periods, and it is common to induce
ventricular tachycardia by mechanical contact of the catheters.40
Genetic Bases and Indications for Genetic Testing
When the SQTS was described initially, investigators tested
if the same genes implicated in the LQTS also could have a
role in the pathogenesis of the SQTS. Indeed, mutations on
2 LQTS genes, KCNH2 and KCNQ1, were found in patients
affected by SQTS.41,42 In vitro functional studies revealed
that SQTS mutations determine a gain of function of the IKr
or IKs channel, respectively, thus increasing the repolarizing
potassium current and shortening repolarization. Therefore, as
in the case of LQT3 and BrS, the SQTS and LQTS are allelic
diseases. In 200543 our group identified the KCNJ2 gene,
which encodes for the channel for the inward rectifier IK1
current, as the third gene that causes SQTS. Interestingly, in
the first patients identified with SQT3 the T wave morphology
differed from that described for the other 2 forms of SQTS,
showing an asymmetrical shape, with a normal ascending
phase followed by a rapid terminal end.
At present, very few SQTS patients have been diagnosed
and genotyped (Table 1); therefore, genetic testing contributes
to clinical management to confirm the diagnosis and to facilitate identification of affected family members.
Catecholaminergic Polymorphic
Ventricular Tachycardia
Catecholaminergic polymorphic ventricular tachycardia
(CPVT) is a peculiar channelopathy linked to mutations on
genes implicated in the regulation of intracellular calcium
homeostasis.44,45 The study of the disease and of its arrhythmogenic mechanisms recently has provided important advancements that also could be applied to acquired cardiac conditions
presenting with calcium disregulation.
Clinical Aspects and Diagnosis
Catecholaminergic polymorphic ventricular tachycardia manifests with stress-induced syncope and cardiac arrest, leading
often to SCD.44,46,47 Occasionally, idiopathic VF also could be
the first clinical manifestation of the disease. The mean age of
onset of symptoms is approximately 12 years.47,48 These common clinical features often raise issues of differential diagnosis
between CPVT and LQTS with modest prolongation of QT
interval. The importance of distinguishing between the 2 diseases, however, centers on the evidence that CPVT patients
have more severe clinical manifestations than LQTS and present a reduced response to β-blockers4,49 (Figure 4). Additionally,
in CPVT, the role of adrenergic stress in triggering symptoms
is even more relevant than in LQTS because the occurrence of
cardiac arrest at rest is an unusual event in CPVT.
At variance with LQTS, most CPVT patients become symptomatic, and therefore the penetrance of the disease is higher
than that of LQTS. In our historical population of patients
we observed that in the absence of medical therapy, 80% of
patients are symptomatic before age 40.49
In CPVT patients, baseline ECGs are unremarkable, while
the morphology of arrhythmias is peculiar and may orient
the diagnosis. The disease is characterized by bidirectional
VT, a tachycardia in which the QRS complexes of the ectopic beats have a 180° rotation on the frontal plane (Figure 6).
Polymorphic VT is common, too, while monomorphic VT is
much less frequent.47
Despite the fact that the lack of signs in the surface ECG
may affect the diagnosis, the arrhythmias easily are reproducible during exercise stress test in the majority of patients
(Figure 6). There is a typical pattern of arrhythmia development during exercise that progresses from the occurrence of
supraventricular and ventricular beats or couplets toward the
Cerrone et al Clinics of Inherited Arrhythmias 587
Figure 6. Treadmill stress test in 1 patient with
catecholaminergic polymorphic ventricular
tachycardia eliciting the hallmark bidirectional
ventricular tachycardia.
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development of bidirectional polymorphic VT. Arrhythmias
usually promptly decrease at the interruption of exercise.
Interestingly, supraventricular arrhythmias and short runs of
atrial fibrillation are common and may facilitate the onset
of ventricular arrhythmias. For this reason, exercise test and
Holter monitoring are important diagnostic tools and also are
useful to monitor the course of the disease and the antiarrhythmic efficacy of medical therapy.
The mainstay of treatment of CPVT is represented by
β-blockers. Even though therapy often is increased to the
maximal tolerated dose, the incidence of recurrences is high,
around 30% to 40% (Figure 4), and therefore consideration of
additional treatments becomes indicated.47,49 Considering the
high lethality of the disease, and the evidence that often SCD
may be the first manifestation, CPVT is an IAD in which the
use of ICD in primary prevention often is considered when
β-blockers fail to control arrhythmic episodes. Recent studies
derived from experiments in animal models suggest that flecainide could be an effective addition to β-blockers in limiting
the arrhythmias.50–52 One clinical trial [NCT01117454] is now
ongoing to investigate the efficacy of flecainide in addition
to standard therapy in patients with an ICD. This study will
be important in assessing the beneficial effect of flecainide
therapy as an alternative or in combination with β-blockers.
Even though the disease has a genetic etiology, most
reported cases are sporadic. This could be attributed to its high
lethality and to the fact that patients may not reach reproductive age unless correctly diagnosed and effectively treated.
When the disease is observed in familial cases there often is
family history for juvenile SCD during adrenergic stress that
may help in the diagnosis.
Genetic Bases and Indication to Genetic Testing
Catecholaminergic polymorphic ventricular tachycardia
can present with an autosomal dominant or with an autosomal recessive transmission. Our group identified in 2001
the gene involved in the more common, dominant form of
CPVT, the RyR2 gene, which encodes for the cardiac ryanodine receptor. It is the main protein controlling the release
of calcium from the sarcoplasmic reticulum (SR) during the
cardiac excitation-contraction coupling.44 The rare, recessive
form is caused by mutations on the CASQ2 gene, coding for
calsequestrin, a protein that controls SR calcium by binding
free calcium ions.45 Investigators were prompted in exploring genes coding for SR proteins as a potential substrate
for CPVT by the morphology of arrhythmias. As a matter
of fact, bidirectional VT initially was observed during digitalis toxicity, a condition in which patients experience calcium overload. The discovery of the genetic bases of CPVT
suggested its arrhythmogenic mechanisms, and the study of
knock-in mice demonstrated that in CPVT, as in digitalis toxicity, delayed after depolarizations-induced triggered activity
underlies the arrhythmias.53,54
Mutations on RyR2 cause dysfunction of the channel that
becomes more prone to release calcium from the SR in the
diastolic phase, thus favoring development of delayed after
depolarizations. Similarly, CASQ2 mutations cause calcium
leakage form the SR either by loss of the binding capacity or
by altering RyR2 open probability.
Among IADs, CPVT is one in which the yield of genetic
testing is encouraging, with values of 60% to 70% positive results in the presence of clinical phenotype55 (Table 1;
Figure 7). Once more, extending genetic testing to family
members allows the identification of gene carriers before
they begin developing symptoms, thus allowing the initiation of β-blockers. Gene testing also may be useful for prenatal diagnosis and reproductive counseling. Considering
the malignancy of this condition, the possibility of starting
prophylactic treatment based on the genetic diagnosis bears
important implications in the management of a patient’s
family.
Mutations on the RyR2 gene also have been discovered in
cases of stress-related idiopathic VF,47 even if in these cases a
positive outcome of the test is less likely.55 In the absence of
clinical signs pointing toward a specific condition that could
have caused the adrenergic-mediated cardiac arrest, screening
on this gene may represent a reasonable approach.
Because RyR2 is one of the largest human genes, with
105 exons, it has been advocated56 to limit sequencing of the
gene only to the regions that account for most of the identified mutations. However, data from our laboratory showed
that among 82 RyR2-positive probands, 14% of the probands
had mutations outside the regions conventionally examined.57
Family screening in these cases identified 4 additional gene
588 Circ Cardiovasc Genet October 2012
Genetic testing generally produces a good yield in CPVT,
with an average cost of $9170 per positive test, reduced to
$5263 when the clinical diagnosis is conclusive.55 However,
its use in borderline situations, in the absence of strong
clinical indicators, is less advisable, considering that the
probability of a positive result could decrease from 62%
to 5%.
On the other hand, considering the low yield of genetic
analysis in Brugada syndrome, the cost per positively genotyped individuals is higher than that of other IADs55; therefore, genetic screening mainly is justified in cases with clear
clinical presentations to improve the chances of a positive
outcome.
Conclusions
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The clinicians’ ability to better care for patients continues
to improve as novel genes continue to be identified. The
limiting factor, which was once lack of data, now seems
to be shifting to the costs of testing. Further understanding of the genotype-phenotype correlations not only assists
in improvements in treatment, but more importantly, prevention. The clinicians’ understanding of the importance
of genetic testing in not only diagnosis but in risk stratification, and treatment is paramount. This new knowledge
emphasizes the need of a specialized expertise in the field
of cardiovascular genetics to manage complex information
derived from the clinic, as well as from the basic research
laboratory to grant the patients all the benefits linked to the
genetic results.
Figure 7. Yield and costs of genetic test in long QT syndrome,
Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia, in the presence of clinical phenotype. Data from
Rong B, Napolitano C, Bloise R, Monteforte N, Priori S. Yield of
genetic screening in inherited cardiac channelopathies: how to
prioritize access to genetic testing. Circ Arrhythm Electrophysiol.
2009;2:6-15.
carriers, suggesting that a partial screening of RyR2 could prevent the identification of clinically affected cases, exposing
them to the risk of life-threatening events.
Cost-Effectiveness of Genetic Testing
Genetic screening is clearly an important diagnostic tool in
IADs. Commercial panels for genotyping are now available
in the United States and are penetrating the European market,
rendering genetic screening accessible outside of the dedicated research labs. Its increased diffusion has the advantage
of reducing waiting time and offering expanded panels that
include all rare variants. However, it also has raised costs and
escalated reimbursement issues, thus limiting its concrete
accessibility. To address this issue, we performed a cost-effectiveness analysis of genetic testing in IADs,55 which demonstrated that the use of genetic tests could be reasonable and
cost-effective depending on the disease and the clinical presentation (Figure 7).
In the case of LQTS, in the presence of a definite phenotype the average cost for a test is $8418 United States dollars per positive test and has a yield of 64%. However, the
success rate of the test will decrease to 14% for borderline
phenotype.55
Disclosures
None.
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A Clinical Approach to Inherited Arrhythmias
Marina Cerrone, Samori Cummings, Tarek Alansari and Silvia G. Priori
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 12, 2017
Circ Cardiovasc Genet. 2012;5:581-590
doi: 10.1161/CIRCGENETICS.110.959429
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