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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3849_Библиотеки_им_академика_М_И_Перельмана
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9 Ventricular Tachyarrhythmias
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A. Ojo et al.
Hereditary Arrhythmias
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IdoGoldenberg, AlonBarsheshet,
andDavidT.Huang
Abstract
Ventricular tachyarrhythmias (ventricular tachycardia [VT] or
ventricular brillation [VF]) are associated with syncope,
aborted cardiac arrest (ACA) or sudden cardiac death (SCD).
Patients will experience syncope, ACA, or SCD depending on
the duration of the VT and whether VT degenerates into VF.
The etiology of these life- threatening hereditary arrhythmias can be classied according to whether structural heart
disease is present or not. Structural causes of hereditary
arrhythmias include hypertrophic cardiomyopathy (HCM),
and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Most of the nonstructural causes of hereditary
10
I. Goldenberg
Rochester General Hospital, Rochester, NY, USA
University of Rochester Medical Center, Rochester, NY, USA
A. Barsheshet
The Rabin Medical Center, Tel-Aviv University, Tel-Aviv, Israel
D. T. Huang (*)
University of Rochester Medical Center, Rochester, NY, USA
e-mail: david_huang@urmc.rochester.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
D. T. Huang et al. (eds.), Cardiac Electrophysiology in Clinical
Practice, In Clinical Practice,
https://doi.org/10.1007/978-3-031-41479-4_10
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arrhythmias are cardiac channelopathies (disorders involving
mutations in genes encoding cardiac ion channels) that include
the congenital long QT syndromes (LQTS), Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Inherited inltrative cardiomyopathies, such as
Fabry disease, are also an important cause of arrhythmias.
This chapter will focus on the clinical and genetic aspects of
the LQTS, Brugada syndrome, and ARVC/D, CPVT.It should
be noted that these genetic syndromes exhibit incomplete penetrance (i.e., the likelihood that a disease-causing mutation
will have a phenotypic expression in a mutation- positive subject) and variable expressivity (i.e., different level of phenotypic expression), implicating environmental factors and
possibly other genetic modiers in the etiology of these diseases.
Keywords
Hereditary arrhythmias · Ventricular tachycardia · Long QT
syndrome · Brugada · Torsades de pointes · ARVC/D · Cardiac
devices therapy · Fabry disease
D. Huang et al.
Long QT Syndrome
Introduction
The long QT syndrome (LQTS) is a hereditary arrhythmia syndrome characterized by structurally normal heart and delayed
ventricular repolarization manifested on the ECG as abnormal QT
interval prolongation and T wave abnormalities.
LQTS is commonly associated with syncope, however SCD
can occur due to torsade de pointes. This is a form of polymorphic
ventricular tachycardia that is associated with a prolonged QT
interval preceding the arrhythmia. The estimated prevalence of
LQTS is 1:2000–2500 of apparently healthy live-births [1]. About
85% of the reported cases are inherited from one of the parents,
with the remaining 15% of affected patients having de novo muta-
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tions. There is a slight female predominance that is more prominent after puberty.
The rst descriptions identied two patterns of inheritance:
autosomal dominant and autosomal recessive. The most common
form is the autosomal dominant form, also called Romano-Ward
syndrome. The autosomal recessive form, also called JervellLange- Nielsen syndrome, is a severe form of LQTS associated
with congenital deafness.
To date, over 600 mutations have been recognized in 13 LQTS
genes. Three main genes associated with LQT1, LQT2 and LQT3,
respectively account for 90% of genotype-positive LQTS patients
and about 75% of all patients with LQTS [2].
Importantly, about 40% of patients with genotype-positive
LQTS may have a baseline QRS that is within normal range [3].
The LQTS is a leading cause of SCD in young patients with a
structurally normal heart. Without treatment, the mortality rate
can reach 21% within 1year of the rst episode of syncope [4].
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Mechanism ofLQTS
The molecular mechanisms in LQTS can be associated with
genetic defects that lead to a decrease in repolarizing potassium
currents or increased depolarizing sodium and calcium channels.
These genes mutations lead to abnormal ion channels associated
with prolongation of the myocardial action potential. The prolonged action potential may be explained by at least two mechanisms: (1) it increases the calcium current available sodium
channel reactivation during the repolarizing phase which leads to
the development of early afterdepolarizations and subsequent
triggered activity. (2) it preferentially occurs in the epicardium
compared to the endocardium, resulting in an increase in transmural dispersion of repolarization which in turn, increases the probability of reentrant arrhythmias [4].
A. LQT1
This clinical syndrome is caused by loss of function (LOF)
mutations in KCNQ1, encoding the alpha-subunit of the
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slowly activating potassium channel. This leads to reduced
current of the slow component of the delayed rectier IK current, the most signicant determinant of the cardiac action
potential. In fact most cases of AR JLN Syndrome are caused
by either heterozygous or homozygous mutations in KCNQ1.
B. LQT2
LQT2 is associated with LOF mutations in KCNH2 (Herg),
ultimately leading to reduced rapidly activating potassium
current.
C. LQT3
This is associated with gain of function mutations in
SCN5A which results in increased sodium current during the
plateau and the late phase of the action potential.
D. LQT 4–16
13 genes, in addition to the ones described above, that were
identied account for 5% of clinically diagnosed LQTS.The
mechanism of action of each of these mutations is beyond the
scope of this chapter.
D. Huang et al.
Diagnosis andClassication
The diagnosis of LQTS is based on measurement of the corrected
QT (QTc) on the ECG, clinical history, and/or genetic testing. A
recent expert consensus statement [3] suggested that a diagnosis
of LQTS can be made if one or more of the following criteria are
fullled: (1) In the presence of a very prolonged QTc (≥500ms)
in repeated 12- lead ECG and in the absence of a secondary cause
for QT prolongation; (2) If a prolonged QTc is identied after a
syncopal event in the absence of acquired causes of QT prolongation; (3) In the presence of an LQTS risk score (the SchwartzMoss risk score based on personal and family history,
symptomatology, and ECG) [5] ≥3.5; (4) In the presence of a
pathogenic mutation in one of the LQTS genes.
It should be noted that about 25% of patients with genetically
conrmed LQTS exhibit QTc within normal range [6]. Four major
provocative tests have been proposed to unmask LQTS patients
with normal range QT at rest: (1) change from a supine to stand-
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223
ing position [7], (2) during the recovery phase of exercise testing
[8], (3) infusion of epinephrine [9], or (4) Adenosine-induced,
sudden bradycardia and subsequent tachycardia [10].
LQTS is classied into 13 types according to the identied 13
LQTS associated genes with LQTS types 1–3 being the most
common types of LQTS.LQTS type 1 accounts for 30–35% of
cases of LQTS and involves a loss of function mutation in the
alpha subunit of the slow delayed rectier potassium channel
KCNQ1; the current through this channel is known as I
Ks.
LQTS type 2 accounts for 25–30% of cases of LQTS and
involves loss of function mutations in the alpha subunit of the
rapid delayed rectier potassium channel KCNH2 (or hERG); the
current through this channel is known as I
Kr.
LQTS type 3 accounts for 5–10% of cases of LQTS and
involves a gain of function mutation in the alpha subunit of the
sodium channel SCN5A, the current through this channel is
known as I
Na.
LQTS types 4 through 14 are rare, each type accounts for less
than 1% of cases of LQTS.LQT5 involves a mutation in the beta
subunit KCNE1 (or MinK) which co-assembles with KCNQ1.
LQT6 involves a mutation in the beta subunit KCNE2 (or
MiRP1) which co-assembles with KCNH2. LQT7 involves a
mutation in the potassium channel gene KCNJ2; the current
through this channel is called I
It leads to Andersen-Tawil
K1.
syndrome, which is associated with periodic paralysis and physical abnormalities including short stature, micrognathia, dental
abnormalities, low- set ears, widely spaced eyes, and unusual
curving of the ngers or toes (clinodactyly). LQT8 involves a
mutation in the L type calcium channel encoded by the gene
CACNA1c. It leads to Timothy’s syndrome, which is associated
with a very poor prognosis and also fusion of the ngers or toes
(syndactyly), attened nose, small teeth, autism, and possible
cardiac structural anomalies.
Genetic testing may have an important role in the diagnosis,
risk stratication, and management of carriers of LQTS mutations. Currently, genetic testing is usually performed when there
is a clinical suspicion of LQTS and for conrmatory testing
among family members of identied probands.
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D. Huang et al.
Risk Stratication
Genotype-Phenotype Correlation
Genotype-phenotype correlation in the LQTS has been the most
active line of research among the structurally normal heart diseases. It has been recognized that there is an association between
the genetic background and clinical characteristics of the LQTS
including electrocardiographic features, triggers for cardiac
events, risk stratication and prognosis.
Moss etal. [11] have demonstrated that the ST-T wave repolarization pattern on the ECG differs among the three common
LQTS genotypes. Patients with LQT1 typically have a broadbased T-wave pattern; patients with LQT2 exhibit a low amplitude
bid T-wave, whereas in LQT3, T-wave is usually peaked and late
onset.
Importantly, cardiac events in LQTS were shown to be associated with gene-specic triggers. Patients with the LQT1 genotype
are at a higher risk for arrhythmic events triggered by sympathetic
activation induced by exercise. Among the different types of exercise, swimming was shown to be a specic trigger for LQT1
patients [12, 13]. Patients with the LQT2 genotype are at a higher
risk for arrhythmic events triggered by emotional stress, including
anger, fear, startle, or sudden noise during sleep. Patients with the
LQT3 genotype experience arrhythmic events mostly during
sleep or at rest without emotional arousal.
Risk stratication among non-genotyped LQTS patients relies
on a combined assessment of clinical and ECG factors. Figure10.1
shows a suggested risk stratication scheme for non- genotyped
patients with LQTS. Patients may be classied into three main
risk categories: (1) The very high-risk group includes patients
with a history of ACA and/or spontaneous Torsades de pointes;
these patients require an implantable cardioverter debrillator
(ICD) implantation for secondary prevention of SCD; (2) The
high-risk group includes subjects with history of prior syncope or
QTc>500ms, and (3) the low risk group includes those with QTc
duration of ≤500ms without prior syncope event [2].
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Fig. 10.1 5-yearK-M Rates of ACA or SCD
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Risk stratication among genotyped LQTS patients can be
based on genotype-specic factors found to affect the phenotypic
expression in patients with LQTS; those risk factors include age,
gender, the post partum time period, menopause, prior syncope,
mutation location, type of mutation (missense/ non-missense), the
biophysical function of the mutation and response to betablockers
[14, 15]. Figs. 10.2 and 10.3 show suggested risk stratication
schemes for patients with LQT1 and LQT2, respectively.
The rare forms of LQTS Jervell-Lange-Nielsen syndrome
(autosomal recessive inheritance form of LQTS) and AndersenTawil syndrome (LQTS type 7) are both associated with very poor
prognoses (unless ICD is implanted); Patients with these syndromes experience life threatening arrhythmic events at an early
age. Similarly, patients with multiple LQTS-associated mutations, particularly double mutations affecting the same gene, have
been associated with a greater risk for life threatening arrhythmic
events than patients who harbor a single mutation [16].
Gender andRisk ofArrhythmias
As mentioned above, there is a slight female predominance in
patients with LQTS.Additionally, among patients already diagnosed with LQTS, prior studies have shown that there is an
Rate of ACA/SCD in LQT1 Females by Mutation-Locationa
Probability of ACA/SCD
Probability of ACA/SCD
C-loop 78
123 (0.18)
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226
0.40
Unadjusted P<0.001
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0
Patients at Risk
Other 502
C-loop 99
Rate of ACA/SCD in LQT1 Females by Mutation-Locationb
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
Patients at Risk
Other 372
10 20 30 40
447 (0.01)
89 (0.04)
Unadjusted P=0.33
0
10 20 30 40
306 (0.05)
70 (0.05)
Age
349 (0.05)
71 (0.09)
207 (0.12)
44 (0.17)
Age
C-loop
283 (0.08)
52 (0.18)
C-loop
Other
Other
156 (0.16)
35 (0.21)
D. Huang et al.
207 (0.12)
37 (0.31)
23 (0.24)
Fig. 10.2 Kaplan-Meier estimates of the cumulative probability of aborted
cardiac arrest or sudden cardiac death in (a) women with LQT1 and (b) men
with LQT1, by mutation location. ACA = aborded cardiac arrest; C-loop
mutations=cytoplasmic-loop mutations; LQT1=long QT syndrome type 1;
SCD=sudden cardiac death
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