Inherited Arrhythmia

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Nat Rev Dis Primers. Author manuscript; available in PMC 2021 March 06.
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Published in final edited form as:

Nat Rev Dis Primers. ; 6(1): 58. doi:10.1038/s41572-020-0188-7.
Inherited cardiac arrhythmias

Peter J. Schwartz1,2,✉, Michael J. Ackerman3,4,5, Charles Antzelevitch6,7, Connie R.
Bezzina2,8, Martin Borggrefe9,10, Bettina F. Cuneo11, Arthur A. M. Wilde2,8,12
1IstitutoAuxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and
Laboratory of Cardiovascular Genetics, Milan, Italy. 2European Reference Network for Rare and
Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART), Bruxelles, Belgium.
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3Department of Cardiovascular Medicine/Division of Heart Rhythm Services, Mayo Clinic,
Rochester, MN, USA. 4Department of Pediatric and Adolescent Medicine, Division of Pediatric
Cardiology, Mayo Clinic, Rochester, MN, USA. 5Department of Molecular Pharmacology &
Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo
Clinic, Rochester, MN, USA. 6Lankenau Institute for Medical Research and Lankenau Heart
Institute, Wynnewood, PA, USA. 7Sidney Kimmel Medical College of Thomas Jefferson University,
Philadelphia, PA, USA. 8Amsterdam UMC, University of Amsterdam, Heart Center; Department of
Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam,
Netherlands. 91st Department of Medicine, University Medical Center Mannheim, Mannheim,
Germany. 10DZHK (German Center for Cardiovascular Research), Partner Site Mannheim,
Mannheim, Germany. 11Department of Pediatrics, Division of Cardiology, Children’s Hospital
Colorado, Aurora, CO, USA. 12Columbia University Irving Medical Centre, New York, NY, USA.
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Abstract
The main inherited cardiac arrhythmias are long QT syndrome, short QT syndrome,
catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome. These rare
diseases are often the underlying cause of sudden cardiac death in young individuals and result
from mutations in several genes encoding ion channels or proteins involved in their regulation.
The genetic defects lead to alterations in the ionic currents that determine the morphology and
duration of the cardiac action potential, and individuals with these disorders often present with
syncope or a life-threatening arrhythmic episode. The diagnosis is based on clinical presentation
and history, the characteristics of the electrocardiographic recording at rest and during exercise
and genetic analyses. Management relies on pharmacological therapy, mostly β-adrenergic
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✉
p.schwartz@auxologico.it.
Author contributions
Introduction (P.J.S.); Epidemiology (P.J.S. and C.R.B.); Mechanisms/pathophysiology (P.J.S., C.R.B., C.A., A.A.M.W., M.B. and
M.J.A.); Diagnosis, screening and prevention (P.J.S., A.A.M.W., M.B. and M.J.A.); Management (P.J.S., A.A.M.W., M.B., M.J.A. and
B.F.C.); Quality of life (P.J.S., A.A.M.W. and M.J.A.); Outlook (P.J.S., A.A.M.W., M.B. and M.J.A.); Overview of Primer (P.J.S.).
Competing interests
M.J.A. is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia and St. Jude
Medical, and holds equity/royalties of AliveCor, Blue Ox Health and StemoniX. C.A. is a consultant for Novartis Institutes for
BioMedical Research, Inc. and Trevena, Inc. All other authors declare no competing interests.
Peer review information
Nature Reviews Disease Primers thanks J. Kanters, R. Kass, H. Morita, S. Nattel, S. Ohno, Y. Rudy, K. Shivkumar, M. Yano and the
other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Schwartz et al. Page 2
receptor blockers (specifically, propranolol and nadolol) and sodium and transient outward current
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blockers (such as quinidine), or surgical interventions, including left cardiac sympathetic

denervation and implantation of a cardioverter–defibrillator. All these arrhythmias are potentially
life-threatening and have substantial negative effects on the quality of life of patients. Future
research should focus on the identification of genes associated with the diseases and other risk
factors, improved risk stratification and, in particular for Brugada syndrome, effective therapies.
The field of inherited arrhythmic disorders is bursting with novel information and data,
ranging from genetic findings to advances in diagnosis and risk stratification to progress in
personalized — even gene-specific — management. Currently, the greatest interest and
challenge concerns the so-called ion channelopathies — inherited conditions related to
primary electrical disorders in the setting of a structurally normal heart. These diseases are
caused by mutations in genes encoding ion channels. Of note, other types of inherited
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arrhythmias exist, such as hereditary atrial fibrillation and arrhythmogenic right ventricular
cardiomyopathy. This Primer focuses on the four major channelopathies: long QT syndrome
(LQTS), short QT syndrome (SQTS), catecholaminergic polymorphic ventricular
tachycardia (CPVT) and Brugada syndrome (BrS). These four clinical entities share several
features: they have an overall low prevalence, their diagnosis is not always simple and they
can be fatal. The fact that all these diseases have the potential to trigger life-threatening
arrhythmias increases the responsibilities and the concerns of the clinicians who see patients
with these conditions only occasionally owing to their rarity, and are, therefore, often ill at
ease in taking clinical decisions that may be difficult or impossible to reverse.
Following a brief overview of epidemiology, genetics and underlying electrophysiological

mechanisms, this Primer focuses on the clinical aspects of diagnosis, risk stratification and
therapy, including — whenever appropriate — gene-specific management. The pregnancy-
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associated risks are considered, as well as the effects of these diseases on the quality of life
of the patients. Finally, a large reference section provides the interested readers with the
sources for the statements presented in this document.
Epidemiology
Studies investigating sudden cardiac death (SCD) in young individuals (of <35 years of age),
conducted in the USA, Denmark and the Netherlands1–3, have estimated an incidence in this
age group of 1.3–3.2 per 100,000 person-years. A 2016 3-year, prospective, population-
based study of SCD among persons of 1 to 35 years of age in Australia and New Zealand
uncovered a higher prevalence of SCD in males than females and found that SCD occurred
predominantly during sleep (38%) or at rest (27%)4. At autopsy, a structurally normal heart
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was found in 40% of cases, suggesting a possible primary electrical disorder caused by ion
channel dysfunction, such as LQTS, SQTS and CPVT, as the cause of death4. Coronary
artery disease and inherited cardiomyopathies were established as probable cause of death in
24% and 16% of cases, respectively4. The incidence of SCD in this age group (<35 years) is
much lower than that observed in the general population. Studies in the USA and the
Netherlands have reported a yearly incidence of 0.6 to >1.4 per 1,000 individuals in the
general population5,6. At the general population level, the average age at SCD is 65 years,
around 75% of individuals are male7, and coronary artery disease and its consequences,
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including acute myocardial ischaemia and heart failure, are the cause of SCD in about 80%
of cases8.
The cardiac channelopathies that can be associated with SCD are rare, especially SQTS.
Systematic population-based studies are lacking, and the real prevalence of these disorders is
largely unknown, with the notable exception of LQTS. As a consequence, the numbers
reported in articles and reviews, including guidelines (for example, the figure of 1 per
10,000 individuals for CPVT9), are at best educated guesses. Regarding LQTS, a prospective
electrocardiogram (ECG) study was performed in 44,596 infants of 15–25 days of age (of
whom 43,080 were white individuals)10. Whenever the first corrected QT (QTc) interval
measured exceeded 450 ms, a second ECG was repeated within 1–2 weeks. If QT
prolongation was confirmed and QTc exceeded 470 ms (at the beginning of the study) or
460 ms (towards the end of the study, when the cut-off threshold for genetic tests was
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lowered), genetic analysis was performed. Disease-causing mutations were identified in 29%
of the infants with a QTc between 451 and 460 ms and in 49% of those with a QTc >470 ms.
Overall, 17 of 43,080 white infants were diagnosed with LQTS, demon-strating a prevalence
of at least 1 in 2,534 apparently healthy live births (95% CI, 1 in 1,583 to 1 in 4,350). As
genetic analyses were not performed for infants with a QTc between 450 and 470 ms, it was
suggested that the actual prevalence of LQTS with a positive ECG phenotype is at least 1 in
2,000 individuals10.
Founder mutations causing primary electrical disorders have been described in certain
geographical regions. For example, LQTS founder mutations have been reported in
Finland11, South Africa12, Canada13, the Netherlands14 and Sweden15. In such regions, the
prevalence of the disorder is expected to be higher than in other areas. Knowledge
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concerning ethnic differences in the prevalence of these arrhythmias is limited, as most of

the patient cohorts studied originated from the Western world and, to a lesser extent, from
Asian countries. Ethnic differences have been observed for BrS, as ECG studies showed that
the prevalence is higher among Asians (0.0–0.94%) and Japanese–Americans (0.15%) than
in Europeans (0.0–0.02%) and North Americans (0.005–0.1%)16. However, complete figures
regarding precise estimates of BrS are lacking, as in individuals with suspected BrS but
without a spontaneous type I ECG, the diagnosis cannot be confirmed without additional
investigations (such as, for example, drug challenge during ECG recording)17 (see
Diagnosis, screening and prevention).
Mechanisms/pathophysiology
The great majority of genes identified to date as being associated with the primary electrical
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disorders encode the crucial cardiac ion channel pore-forming α-subunits or proteins that
interact with and regulate ion channels (also known as channel-interacting proteins or
ChIPs) (FIG. 1; TABLE 1).
LQTS genetics
LQTS is most commonly inherited as an autosomal dominant disorder (initially known as
Romano–Ward syndrome). Inherited genetic variations in one of the three major LQTS
susceptibility genes underlie the disorder in ~90% of patients in whom a causative mutation
was identified. Type 1 LQTS (LQT1), caused by genetic variants in KCNQ1 (REF.18)
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encoding the subunit KV7.1 of the voltage-gated potassium channel that is responsible for
the outward potassium current IKs, accounts for ~30–35% of cases19. LQT2, caused by
genetic variants in KCNH2 encoding the pore-forming α-subunit KV11.1 of the voltage-
gated potassium channel responsible for the inward rectifying potassium current IKr20,
accounts for ~25–40% of cases. LQT3 is caused by genetic variants in SCN5A21 encoding
the subunit-α NaV1.5 of the voltage-gated sodium channel responsible for the inward
sodium current INa and represents ~5–10% of cases of LQTS. Approximately 15–20% of
patients with a definite clinical diagnosis of LQTS remain genotype-negative after extensive
genetic testing22. Single-nucleotide variants, small insertions or small deletions are the most
commonly encountered disease-causing variations in these genes19. However, large gene
rearrangements have also been described23. About 5% to 10% of patients with LQTS host
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multiple mutations in these genes, and symptoms typically present at a younger age and with
a more severe phenotype in these patients than in patients with a single mutation24–26.
Genotype–phenotype correlations.—Genotype–phenotype studies in the KCNQ1 and

KCNH2 genetic subtypes have identified relationships between the severity of the disorder
and the type of mutation, the location of the mutation and the extent of functional
derangement of the ion channel. Studies conducted in patients with KCNQ1 defects have
identified that variants at sequences encoding transmembrane regions of the KV7.1 channel
are associated with a higher risk of cardiac events than variants in sequences encoding the
carboxy terminus, and variants that result in a severe reduction of channel function due to a
dominant-negative effect are also associated with a higher risk of cardiac events than
variants that result in haploinsufficiency25. In patients with KCNH2 defects, missense
variants in the sequence encoding the pore region of the KV11.1 channel have been
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associated with more severe clinical manifestations and higher cardiac event rates than those
associated with mutations27 localized outside the pore-coding sequence.
Other LQTS-associated genes.—Several other genes encoding either ion channel

subunits (KCNE1, KCNE2, KCNJ5 and SCN4B) or proteins that regulate ion channel
function (CALM1, CALM2, CALM3, AKAP9, CAV3, ANK2, SNTA1 and TRDN) have
also been implicated in LQTS causality28. However, it should be noted that most of these
genes have been implicated using a hypothesis-driven, candidate gene approach, and,
therefore, the strength of evidence supporting their causality varies widely28. In fact, some
of these genes received a disputed-evidence (KCNE2, KCNJ5, SCN4B, SNTA1, AKAP9
and ANK2) or limited-evidence (CAV3, KCNE1 and KCNJ2) gene designation on
application of the gene-disease association framework of the Clinical Genome (ClinGen)
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Resource28–30. By contrast, CALM1, CALM2, CALM3 and TRDN were found to have
strong (TRDN) or definitive (CALM1, CALM2 and CALM3) evidence.
Patients with LQTS harbouring variants in CALM1, CALM2 or CALM3 (encoding

calmodulin 1, calmodulin 2 and calmodulin 3, respectively) present symptoms early in life
with profound QTc interval prolongation, which may be accompanied by 2:1 atrioventricular
block and a high predisposition for cardiac arrest and sudden death31,32. Calmodulin is a
calcium-sensing, signal-transducing protein that regulates many calcium-dependent

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processes and modulates the function of several cardiac ion channels. CALM1, CALM2 and
CALM3 are located on distinct chromosomes, have a nucleotide sequence homology of
85%, and yet code for a completely identical, 149 amino acid calmodulin protein. Despite
this high redundancy, one mutant allele out of six is sufficient to cause LQTS. Relevant
information is provided by the International Calmodulinopathy Registry33 on 74 patients. In
a series of 29 patients whose family members were genetically screened, the culprit CALM
variant occurred de novo in 93% of cases, and in the remaining cases germline mosaicism
was present in one of the parents33. Patients with homozygous or compound heterozygous
pathogenetic variants in TRDN may manifest either a predominant LQTS or CPVT
phenotype34,35.
Extracardiac manifestations.—Three clinical variants of LQTS manifest with

extracardiac features besides QT interval prolongation. The autosomal recessive Jervell and
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Lange-Nielsen syndrome, characterized by sensori-neural deafness and high arrhythmic risk,

is caused by homozygous or compound heterozygous mutations in KCNQ1 (REF.36) or
KCNE1 (REF.37); KCNE1 mutations are associated with a less severe phenotype than
KCNQ1 mutations38. Timothy syndrome presents with multiorgan dysfunction including
webbing of fingers and toes, congenital heart defects, immune deficiency, hypo-glycaemia,
cognitive abnormalities and autism39. The same recurrent sporadic de novo missense
mutation in CACNA1C (encoding the pore-forming subunit-α CaV1.2 of the voltage-gated
cardiac calcium channel that is responsible for long-lasting (L-type) calcium currents),
which results in the G406R amino acid substitution, accounts for many of the cases reported
to date40, although other missense mutations in this gene have also been reported. However,
mutations in CACNA1C have also been described for autosomal dominant LQTS in the
absence of extracardiac features41. The Andersen–Tawil syndrome, which presents with
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facial dysmorphism and hypokalaemic periodic paralysis, is caused by dominantly inherited

loss-of-function mutations in KCNJ2, which encodes the inward rectifier potassium channel
Kir2.1 (which is responsible for the IK1 current)42. Although Andersen–Tawil syndrome was
initially presented as part of the LQTS spectrum, it has been argued that the QT interval
prolongation in this disorder is erroneously diagnosed by the inclusion of the prominent U
wave abnormality in the QTc calculations28; accordingly, this arrhythmic syndrome should
not be regarded as part of LQTS28.
SQTS genetics
SQTS is inherited as an autosomal dominant disorder. Mutations in three genes encoding
potassium channels, namely, KCNH2 (REF.43), KCNQ1 (REF.44) and KCNJ2 (REF.45),
have been implicated in the disorder and are associated with its subtypes SQT1, SQT2 and
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SQT3, respectively. In contrast to loss-of-function variants associated with LQTS, SQTS-

causing variants in KCNH2, KCNQ1 and KCNJ2 lead to a gain-of-function defect of the
affected potassium channel. Mutations in the L-type calcium channel subunit genes
CACNA1C, CACNB2 and CACNA2D1 (REF.46) have been described in patients presenting
with a shorter than normal QTc or an overlapping phenotype that combines an abbreviated
QTc and a BrS ECG phenotype47, yet evidence for their causality is limited. These
mutations are expected to cause a loss of channel function, thereby also abbreviating the
action potential (AP). The same missense mutation in SLC4A3, encoding the anion
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exchange protein 3 (also known as solute carrier family 4 member 3), has been described in
a large family with SQTS and a smaller, unrelated family48.
CPVT genetics
CPVT is commonly inherited in an autosomal dominant manner. In 65% of CPVT probands,
the disorder is caused by a mutation in RYR2, which encodes the ryanodine receptor 2
(RYR2), a calcium release channel located on the sarcoplasmic reticulum (SR) of
cardiomyocytes49–51, and these individuals have CPVT type 1. RYR2 mutations are
typically missense and cluster predominantly at sequences encoding specific regions of
RYR2, although some mutations still occur outside these clusters52,53. Mutations in CASQ2,
which encodes calsequestrin 2, a protein that binds to free calcium inside the SR, cause
CPVT type 2, a much rarer but more severe autosomal recessive form of CPVT54. Other
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genes involved in calcium homeostasis, namely CALM1 (REF.55) and TRDN56, have also
been implicated as a cause of CPVT. Mutations in CALM2 have been described in patients
with overlapping features of LQTS and CPVT57. Mutations in ANK2 and KCNJ2 that also
cause, respectively, Ankyrin B syndrome (initially called LQT4) and Andersen–Tawil
syndrome have been described in a few patients with normal QTc and exercise-induced
arrhythmias58,59. Furthermore, recessive mutations in TECRL, encoding the trans-2,3-enoyl-
CoA reductase-like protein expressed in the endoplasmic reticulum, have been associated
with a clinical phenotype that has overlapping features of LQTS and CPVT60. The CPVT
genetic test panel should include at least examination of the entire 105 translated exons of
RYR2, CASQ2, KCNJ2, CALM1, CALM2, CALM3, TRDN, TECRL and PKP2 (encoding
plakophilin 2)61. Notably, PKP2-mediated arrhythmogenic right ventricular cardiomyopathy
can have a pre-cardiomyopathic electrical phase of the disease that mimics CPVT62.
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BrS genetics
The only gene thus far unequivocally implicated in BrS is SCN5A63,64. As opposed to
LQTS-associated variants, BrS-associated SCN5A variants are loss of function. At least 20
other genes have been reported for BrS; however, these genes have almost exclusively been
discovered through candidate gene studies in single individuals or small families.
Furthermore, the recent reappraisal of all reported BrS susceptibility genes (either by testing
for an increased burden of rare genetic variants in patients with BrS compared with
controls65 or by the application of the ClinGen evidence-based gene curation framework64)
supports only the involvement of rare variations in SCN5A, which are found in ~20% of
probands65. The largely sporadic presentation of the disorder and the low disease penetrance
in families with rare variants in SCN5A, as well as the observation of phenotype-positive
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genotype-negative individuals in such families, has suggested that BrS is a disorder with an
inheritance more complex than the Mendelian inheritance that was previously considered66.
A genome-wide association study that identified common small-effect susceptibility variants
in the vicinity of SCN5A and HEY2 provided evidence in support of this complex
inheritance67.
Genetic modifiers
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As for most Mendelian disorders, the management of patients with Mendelian primary
electrical disorders is complicated by the variability in clinical severity among patients, even
those carrying the same mutation. Such variability within families is evidenced by low
disease penetrance (the proportion of individuals carrying a variant who show phenotypic
effects), variable expressivity (different severity observed among individuals carrying the
familial genetic defect) and pleiotropy (the phenomenon of a single gene affecting several
phenotypic traits). Variability is observed both in the extent of the ECG abnormality and in
the occurrence of arrhythmic events. Cascade screening and genotyping68,69 has disclosed
that variability in clinical manifestations can be profound, even between siblings with the
same mutations, ranging from a normal ECG and no symptoms to a full-blown phenotype
with life-threatening arrhythmias. An example is the large variability in QTc duration among
individuals harbouring the A341V founder mutation in KCNQ1 causing LQTS12 (FIG. 2). A
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study showed a large spectrum of QTc values in a population of individuals carrying this
mutation, including some values within the physiological range; if QTc prolongation were
determined only by the A341V mutation, the QTc values should be uniformly prolonged
with modest variability12. This observation points to the presence of additional factors
affecting ventricular repolarization.
Factors that modify the clinical expression of Mendelian primary electrical disorders can be
non-genetic, such as age, sex70 and, according to some studies, features of the cardiac
tissues, such as, for example, fibrosis. In addition to non-genetic factors, the inheritance of
other genetic variants, commonly referred to as genetic modifiers, contributes to the
variability in the phenotype71. Genetic modifiers may exacerbate or temper the effect of the
disease-causing mutation, and the net effect of the mutation and genetic and non-genetic
modifiers determines the severity of the ECG defect and/or occurrence of arrhythmias.
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Research into genetic modifiers in these primary electrical disorders is still in its infancy, yet
some associations have started to emerge71, primarily in LQTS71. Moreover, the mechanism
of action of modifier genes is beginning to be unravelled72. The identification of these
associations has been in part facilitated by the availability of large founder populations,
wherein the presence of the same disease-causing mutation favours the identification of
modulatory variants, as it enables the exclusion of interindividual variation stemming from
different primary genetic defects73–76. As more modulatory variants are identified, combined
genotyping for disease-causing mutations as well as for modifiers may enable more refined
risk stratification.
Pathophysiology of the individual arrhythmias

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Characteristics of the cardiac AP.—The cardiac cell, similar to all excitable cells,
maintains a voltage difference between the exterior and interior of the cell — the membrane
potential — of typically −60 to −90 mV, depending on the cell type. Thus, the interior of the
cell has a negative voltage relative to the exterior. When the voltage-gated sodium (in atrial
and ventricular cardiomyocytes) or calcium channels (in nodal cardiac cells) open, the
membrane depolarizes (the membrane potential becomes more positive), giving rise to an
AP. The cardiac AP has a key role in coordinating the contraction of the heart. The cardiac
cells of the sinoatrial node provide the pacemaker potential, which determines the heart rate.
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The APs of these cells propagate through the atria to the atrioventricular node, which is
normally the only conduction pathway between the atria and the ventricles. APs from the
atrioventricular node travel through the bundle of His and then to the Purkinje fibres system
to activate the ventricles in an orderly fashion. Abnormalities in the cardiac AP (due to
congenital mutations, exposure to toxins or drugs or injury) can lead to the development of
cardiac arrhythmias.
There are four phases to the cardiac AP in the contracting atrial or ventricular cardiac cells
(FIG. 3). The sharp depolarization (phase 0) is due to inward movement of sodium ions,
whereas repolarizations (phases 1 and 3) are principally due to outward movement of
potassium ions. During the phase 2 plateau period, the cells are maintained in a depolarized
state achieved through a balance between the inward movement of calcium ions and the
outward movement of potassium ions.
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SDR as a common link in arrhythmogenesis.—The four channelopathies thus far

discussed differ with respect to the characteristics of the QT interval. In LQTS and in SQTS,
the QT interval prolongs or shortens, respectively, as a result of the disease, whereas in BrS
and early repolarization the QT interval remains largely unchanged or abbreviates. However,
these four syndromes have in common an amplification of the spatial dispersion of
repolarization (SDR)77, which results in the development of polymorphic ventricular
tachycardia (VT) and fibrillation when dispersion of repolarization and refractoriness reach
the threshold for reentry. When polymorphic VT occurs in the setting of long QT, it is
referred to as Torsades de Pointes according to its specific morphology. The threshold for
reentry decreases as the AP duration and refractoriness are reduced and the conduction path
length required for establishing a reentrant depolarization wave is progressively reduced77.
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Of note, the conduction path length required for establishing reentry is also importantly
influenced by conduction velocity, such that reentry is facilitated when conduction is
slowed. It has to be said that the hypothesis supporting a major role of SDR has largely
originated from experiments in canine wedge preparations78, with interpretations that are not
uniform; indeed, several electrophysiologists have different views as to the arrhythmic
substrate in some of these conditions79.
LQTS.—In LQTS80–82, a reduction of net repolarizing current secondary to loss of function

of outward potassium channel currents or gain of function of inward currents underlies the
prolongation of the myocardial AP and QT interval that attend both congenital and acquired
LQTS83–85. Acquired LQTS is most of the time secondary to drugs that have an IKr-
blocking effect86. Accentuation of SDR and refractoriness within the ventricular
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myocardium, secondary to exaggerated trans-septal or transmural dispersion of

repolarization, has been identified as the principal arrhythmogenic substrate in LQTS87,88.
This exaggerated intrinsic heterogeneity together with early afterdepolarization-induced
triggered activity, both caused by a reduction in net repolarizing current, underlie the
substrate and trigger the development of Torsades de Pointes observed in LQTS87. The
mechanism underlying Torsades de Pointes has been a matter of debate for many years. In
addition to reentrant activity, early afterdepolarization-mediated focal activity has been
proposed. Although short episodes of Torsades de Pointes may be due to focal activity,
longer and non-terminating episodes are always maintained by reentrant activity89.
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SDR is further exaggerated by sympathetic influences, especially in LQT1 and LQT2,

accounting for the great sensitivity of these patients to adrenergic stimuli. It is important to
keep in mind that neurally mediated sympathetic activation acts through release of
noradrenaline at the neural terminals in the ventricles, which has consequences different
from those produced by blood-borne catecholamines, and the effects of noradrenaline as a
neurotransmitter are different from those produced by circulating catecholamines. Locally
released noradrenaline increases the heterogeneity of repolarization and facilitates
ventricular fibrillation90; this effect is very different from that of adrenaline and,
experimentally, of isoprenaline (a β-adrenergic receptor agonist).
SQTS.—SQTS is an extremely rare channelopathy, characterized by pathologically

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accelerated repolarization resulting in very short QT intervals and the appearance of tall
peaked T waves on the ECG. The augmented Tpeak–Tend interval associated with this ECG
feature suggests that SDR underlies the arrhythmogenic substrate in the ventricles.
Experimental studies suggest that the abbreviation of AP duration in SQTS is
heterogeneous, owing to preferential abbreviation in the epicardium and resulting in an
increase in SDR. Dispersion of repolarization and refractoriness serve as substrate for
reentry, as they promote unidirectional conduction block. Marked abbreviation of
wavelength is an additional factor promoting the maintenance of reentry. Abbreviation of AP
duration and effective refractory period and amplification of SDR also predispose to the
development of atrial fibrillation by creating the substrate for reentry91.
Recent studies involving computational modelling of SQTS92, induced pluripotent stem cell
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cardiomyocytes (iPS-CMs) isolated from patients with SQTS that recapitulate the SQTS
cellular phenotype93–96 and data from a transgenic rabbit model of SQT1 have provided
useful insights into arrhythmogenesis and arrhythmia substrates in SQTS consistent with
previous findings. Nevertheless, there is no clear understanding of the mechanism
underlying the premature ventricular contractions (PVCs) that precipitate polymorphic VT
in SQTS.
CPVT.—Mutations in RYR2, calsequestrin 2 (a calcium-binding protein that acts as a

calcium buffer within the SR), calmodulin and triadin, which underlie CPVT, all lead to
abnormal regulation of cellular calcium homeostasis97,98. This disruption leads to excessive
calcium accumulation (overload) in the SR and spontaneous release of calcium from the SR
in the cytoplasm, causing augmentation of transient inward current and the development of
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delayed afterdepolarizations. Several lines of evidence point to delayed afterdepolarization-

induced triggered activity as the mechanism underlying mono-morphic or bidirectional VT
in patients with CPVT. Sympathetic influences greatly amplify the calcium dysregulation,
leading to precipitation of episodes of CPVT during exercise and accounting for the respon-
siveness of patients to β-adrenergic receptor blockade and sympathetic denervation99,100.
Several studies have reported that abnormal calcium handling can result from missense
mutations or post-translational modification, including oxidation and S-nitrosylation, and
several plausible mechanisms have been proposed — for example, defective RYR2
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interaction with peptidyl-prolyl cis–trans isomerase (FKBP) proteins owing to

phosphorylation of RYR2 at serine 2808 by cAMP-dependent protein kinase A,
phosphorylation of RYR2 at serine 2814 by calcium/calmodulin-dependent protein kinase
type II, store overload-induced Ca2+ release, defective intrasubunit domain interaction in
RYR2 (domain unzipping) or disruptions in calsequestrin 2 (REF.53). Finally, defective
calmodulin binding to RYR2 has also been shown to be crucial to induce CPVT101–103.
The ectopic activity originating from the epicardium is associated with an increased Tpeak–
Tend interval and augmented SDR due to reversal of the normal activation sequence across
the ventricular wall. The increased SDR in turn creates the substrate for reentry, permitting
the induction of polymorphic VT104. Propranolol (a β-adrenergic receptor blocker) and
verapamil (an L-type calcium channel blocker) suppressed all arrhythmic activity in
experimental wedge preparations104. Thus, an accentuation of SDR may play a key part in
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the transition of bidirectional VT to polymorphic VT and ventricular fibrillation in the

setting of CPVT. However, a different conclusion comes from a study in transgenic mice,
which provided evidence that the His–Purkinje system can be an important source of
delayed afterdepolarization-induced triggered activity giving rise to focal arrhythmias in
CPVT98,105. Currently, we are left with these two hypotheses.
BrS.—Prominent J waves in the ECG are associated with BrS and early repolarization. The
electrocardiographic J wave is the result of a transmural voltage gradient created by the
presence of a transient outward potassium current (Ito) mediated by the potassium voltage-
gated channel subfamily D member 3 (also known as KV4.3) that creates a notch in the
shape of the AP — that is, in the first part of phase 2, in the ventricular epicardium but not
the endocardium106–108 (FIG. 4). The transmural gradient and associated J wave is much
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greater in the right ventricle than in the left ventricle, particularly in the region of the right
ventricular outflow tract (RVOT), because of a more prominent Ito-mediated AP notch in the
right ventricular epicardium109. This distinction explains why BrS is a right ventricular
disease. The RVOT origin of BrS could also be attributed to the reduced expression of gap
junctions and sodium channels110. By contrast, in the left ventricle, Ito is most prominent in
the inferior wall, accounting for why early repolarization occurs in the left ventricle, with the
most prominent J point elevation appearing in the inferior ECG leads111. The cellular
mechanism underlying early repolarization is similar to that of BrS111. The principal
difference is the region most involved in generating the arrhythmogenic substrate: the
epicardial cells in the left ventricular inferior wall are most susceptible to early
repolarization owing to a high density of KV4.3 channels111. Using ECG imaging
techniques, a study demonstrated markedly abbreviated activation–recovery intervals and
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marked dispersion of repolarization in the inferior and lateral regions of the left ventricle in
patients with early repolarization112. However, recent epicardial mapping data demonstrate
abnormal conduction (fractionated epicardial signals — that is, multiple deflections in the
QRS complex) in 75% of the patients with early repolarization79. The authors concluded
that these data demonstrate that two distinct substrates — delayed depolarization and
abnormal early repolarization — underlie inferolateral J wave syndromes (A.A.M.W.). This
interpretation is challenged by data showing that, in experimental models of the J wave
syndromes, fractionated ECGs giving rise to J waves are due to delayed repolarization, as
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discussed below (by C.A.).
The ionic and cellular mechanisms underlying BrS have long been a matter of debate113,114.
Two principal hypotheses have been proposed, the repolarization hypothesis and the
depolarization hypothesis. These two hypotheses are next presented by their two proponents,
respectively C.A. and A.A.M.W. These arguments and observations notwithstanding, it
stands to reason that the repolarization and depolarization hypotheses are not mutually
exclusive and may indeed be synergistic. The repolarization hypothesis, also alluded to in
the previous paragraph, asserts that an outward shift in the balance of currents at the end of
phase 1 of the right ventricular epicardial AP, due to genetic mutations in genes encoding
ion channels, generates the BrS ECG phenotype and the underlying repolarization
abnormalities (that is, a heterogeneous loss of the epicardial AP dome) responsible for the
development of both the epicardium to endocardium gradient and transmural SDR. These
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repolarization abnormalities could lead to the development of reentry during phase 2 of the
AP, thereby generating closely coupled premature beats, which can trigger polymorphic VT
or ventricular fibrillation. By contrast, the depolarization hypothesis maintains that fibrosis
and reduced expression of gap junction α1 protein (also known as connexin 43) and sodium
channels in the RVOT110 lead to discontinuities in conduction that are responsible for the
development of the ECG and arrhythmic manifestations of BrS.
C.A.—In BrS, the amplitude of J waves, typically appearing as type I ST segment elevation,
diminishes at fast heart rates, owing to reduced availability of Ito, consistent with the
repolarization hypothesis113,115. The ability of agents such as quinidine (a sodium channel
blocker and a blocker of Ito) to reduce ST segment elevation and exert an ameliorative effect
in BrS is likewise attributable to a reduction in Ito. These observations lend support to the
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repolarization hypothesis, as does the demonstration of a lack of conduction delay in the

RVOT in a whole heart experimental model of BrS116 and the demonstration of an
ameliorative effect following radiofrequency ablation of RVOT, a procedure that destroys the
epicardial cells with the most prominent Ito-mediated AP notch117–119.
A.A.M.W.—In every debate on the pathophysiological substrate of the ST segment elevation

in the right precordial ECG leads, the ability of quinidine to reduce ST segment elevation is
prominently mentioned (see also the previous paragraph). This argument seems valid, given
that the sodium blocking activity of quinidine is expected to be detrimental (that is,
increasing the level of ST segment elevation), but it is also important to consider that the AP
morphology is a crucial determinant for the safety of conduction. This factor is particularly
relevant in areas where conduction is potentially hampered — for example, in areas with
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substantial fibrosis (such as the RVOT in patients with BrS)119 and in Purkinje–ventricular
junctions. Hence, every intervention that alters the AP morphology (for example, decreases
in Ito or any other early potassium current or an increase in ICa, among others) can improve
the safety of conduction120,121 and, therefore, can be compatible with the depolarization
hypothesis. Quinidine blocks Ito and, therefore, can increase the safety of conduction in
regions in which conduction is compromised.
Diagnosis, screening and prevention

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Clinical manifestations
LQTS.—Patients with LQTS may remain without symptoms throughout their life or may
become symptomatic. Most symptomatic patients have their first arrhythmic event during
the first 20 years of life, individuals with LQT1 or Jervell and Lange-Nielsen syndrome
earlier than those with LQT2 or LQT3; at variance with males, females remain at risk
throughout life122. The main clinical manifestations are syncopal episodes, cardiac arrest
and SCD123,124. These events are due to Torsades de Pointes VT, which often degenerates in
ventricular fibrillation. The occurrence or absence of arrhythmic events in a patient with a
disease-causing mutation does not predict what may happen in their offspring125, with the
exceptions of specific genetic variants that are associated with very high126 or very low127
clinical severity.
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Most symptomatic patients show a distinct prolongation of the QT interval, which is often
accompanied by a bizarre morphology of the T wave128,129. The arrhythmic risk increases
significantly when QTc is >500 ms (REF.70) and especially when episodes of T wave
alternans are observed130. Specific triggers for arrhythmic events in patients with LQTS
have been identified; namely, swimming, running, unexpected noises (such as the telephone
ringing, an alarm clock and thunder) or being frightened131. The identification of the LQTS-
associated genes has revealed that, at variance with all other channelopathies, there is a
strong genotype–phenotype correlation in the three LQTS subtypes, a correlation that is
especially important for the recognition of the conditions that may trigger the
arrhythmias122. Patients with LQT1 are at increased risk whenever sympathetic activity
increases, as during emotional or physical stresses, especially swimming122,132. Patients
with LQT2 are at increased risk when exposed to sudden noises, especially if they are at rest
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or asleep and are woken up abruptly; of note, sleep is not a homogeneously quiet state, as
during rapid eye movement sleep there are bursts of both vagal and sympathetic activity that
can be quite arrhythmogenic. Individuals with LQT2 are also very sensitive to low plasma
levels of potassium, and female patients are at high risk during the postpartum period133,134,
probably because of sleep disruption. Finally, patients with LQT3 are at risk primarily when
they are at rest or asleep. Independently of the genotype, infants who have a cardiac event in
the first year of life are at an especially high risk of mortality and often are not protected by
the traditional therapies135. LQTS, as well as all other channelopathies, can contribute to
sudden death in infancy. Almost 10% of infants who die suddenly in the first year of life
carry LQTS-causing mutations136,137, and a prolonged QT interval in newborn babies
increases the risk for sudden death138. It is evident that, without genetic testing, an infant
who died suddenly in the first months of life would be labelled as a case of sudden infant
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death syndrome139,140. These data have conceptual implications. On one hand, they
strengthen the rationale for wide-spread ECG screening in the first month of life10,138, with
the objective to identify infants with LQTS who are at risk of dying in the first year of life or
later141; on the other hand, they call for great restraint before assuming that recurrent sudden
deaths in infancy always imply infanticide.
SQTS.—To date, just over 200 patients have been reported to have SQTS, and most clinical
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data come from two relatively large studies142,143. In both studies, a male predominance was
reported, but the risk of cardiac arrest was similar in both sexes. Although the majority of
patients with SQTS are symptomatic, SQTS may also be diagnosed in asymptomatic
patients during family screening or as an incidental finding during routine ECG or during
sport pre-participation screening. One study142 reported the long-term outcome of 53
patients with SQTS from the European Short QT registry (75% male, median age 23 years,
follow-up period 64 ± 27 months); 62% of patients were symptomatic at presentation. The
most common presenting symptom was cardiac arrest (33%). Most cardiac arrest events
(>90%) occurred between 14 and 40 years of age in male patients. Thirteen patients (24%)
had palpitations, and in six of these patients atrial fibrillation or atrial flutter were
documented; eight patients (15%) had syncope. Atrial fibrillation was noted already in
newborn babies and young children.
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The second study143 included 73 patients with SQTS (84% male; mean age 26 ± 15 years,
follow-up 60 ± 41 months); 53% of patients (n = 39) were symptomatic at presentation, and
SCD or non-fatal sudden cardiac arrest (40%) were the most common presenting
symptoms143. The second most common symptom was syncope (19%). The rate of cardiac
arrest was 4% in the first year of life. The annual event rate was 1.3% between 20 and 40
years of age, and 40% of patients experienced a cardiac arrest by 40 years of age
(cumulative probability of an annual event rate 0.9%). There was no reported trigger of
cardiac arrest, and in 83% of patients cardiac arrest occurred during rest.
CPVT.—Phenotypically, CPVT most closely mimics LQT1, with adrenergic-triggered

syncopes, seizures, sudden cardiac arrest or SCD. In fact, many patients with CPVT had
been previously misdiagnosed with either atypical LQTS or exercise-triggered epilepsy49,99.
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Although CPVT can manifest at any time, sentinel events are most likely to occur during the
first two decades of life and are uncommon after 40 years of age. Thus, CPVT should be
suspected in any patient with a structurally normal heart and a normal resting ECG with a
normal QT interval who experiences a sudden faint, seizure or cardiac arrest during exercise,
exertion or emotional stress (positive or negative). In fact, in these settings, CPVT would be
more plausible as the root cause than LQT1 with a normal QT interval.
Although it has been reported, CPVT is rarely the cause of sudden infant death
syndrome136,137,144. By contrast, CPVT is one of the most common genetically identifiable
explanations for sudden unexplained death in individuals of 1–35 years of age in whom
autopsy results did not show structural heart defects, especially if the death occurred during
exertional activity, particularly swimming145,146. In an otherwise unexplained drowning or
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near drowning, CPVT should be explored as a possibility. In addition, CPVT should be

investigated in patients diagnosed previously with an exertion-triggered generalized seizure
disorder, especially if the epilepsy diagnosis had been accompanied by a normal electro-
encephalogram. CPVT also contributes to idiopathic ventricular fibrillation as shown in a
genetic study in 76 survivors that documented that disease-causing mutations were present
in 7% of cases147.
BrS.—The most frequent clinical manifestations of BrS include a type 1 ECG (see
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Diagnosis) and malignant ventricular arrhythmias148,149, more specifically rapid

polymorphic VT or ventricular fibrillation, typically initiated by extrasystoles from the
RVOT region. Rarely, isolated ectopic beats (most commonly with a left bundle branch
block or inferior axis deviation morphology on the ECG) or non-sustained ventricular
arrhythmias are observed. However, some patients with BrS may report syncopal events,
which are probably caused by self-terminating arrhythmias and lead to an increased risk of
malignant arrhythmias (see below). Arrhythmic events occur typically during the night150.
Supraventricular arrhythmias, most often atrial fibrillation, have been recognized as part of
the BrS phenotype since they were first described as a separate clinical entity148. The
prevalence of atrial fibrillation may be as high as almost 40% in certain cohorts151. The first
symptoms typically occur in the third to fourth decade of life (both in men and women);
however, they can also occur in children and in individuals of >50 years of age152. Fever is a
specific trigger for symptoms, particularly in the paediatric subgroup153,154. Males are more
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frequently affected than females, as shown by every study.
Three morphologies of the BrS ECG pattern have been described. Type 1 is characterized by
a high J point with a coved-type ST segment in the right precordial ECG leads, often
followed by a terminal negative T wave. Type 2 ECG has a saddle-back-shaped ST segment,
with an elevation of ≥2 mm, and type 3 has a saddle-back type or a coved ST segment with
an elevation of <2 mm. Another characteristic ECG feature is the presence of minor
conduction delay at all cardiac levels, manifested by slight PR prolongation, QRS widening
(fractionation) and an abnormal electrical axis, which can be either leftward (manifesting
with a wide “S” in lead I) or rightward. Conduction delay occurs in particular in the
presence of a loss-of-function sodium channel mutation155, which underlies the disease in
approximately 20% of cases156.
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Risk stratification in asymptomatic patients with BrS is ill defined. Most studies are
retrospective in nature, and no single parameter, with the exception of a spontaneous (that is,
not induced by administration of sodium channel blockers or fever) type 1 ECG, has
consistently been shown to predict risk of malignant arrhythmias157. An asymptomatic
patient with a spontaneous type 1 ECG has a yearly risk of ~1% to present with malignant
arrhythmias, and such risk may or may not be considered sufficient to warrant the implant of
an implantable cardioverter–defibrillator (ICD), whereas the risk in symptomatic patients is
~3–7% per year, depending on the presenting symptom. Probably the most reliable risk
factor is a (progressive) fractionated ECG in the right precordial leads157. Programmed
electrophysiological stimulation (that is, stimulation of the heart by intracardiac catheters
following a predesigned stimulation protocol) may help to estimate the risk, provided a low-
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intensity protocol is used158.
Diagnosis
LQTS.—The diagnosis of typical cases (such as a youngster who experienced a syncope
during emotional or physical stress and has a prolonged QT interval) is quite
straightforward. The upper limits of normal QTc (with Bazett’s correction) are 440 ms for
males and 460 ms for females. The normal mean QTc is 400 ± 20 ms. Accidental diagnoses
are often triggered by medical visits and ECG ahead of participation in sports, especially in
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countries such as Italy where these visits are mandatory by law. In asymptomatic
individuals, especially when the QT interval is only modestly prolonged, the diagnosis is
more complex and requires experience and additional tests. To help clinicians, a diagnostic
score has been developed and upgraded over the years80,124,159,160 (BOX 1). The accurate
measurement of the QTc duration at rest is most informative both for diagnosis and
prognosis. More and more frequently the so-called tangent method is used, on the basis that
it facilitates the identification of the point where the descending limb of the T wave crosses
the baseline. However, this method is actually misleading whenever the descending limb of
the T wave has a slow component, which happens often when there is an impairment of IKs
and IKr. The tangent method can, therefore, lead to an underestimation of the QT interval
and should not be used when there is a suspicion of LQTS. The morphology of the T wave is
also indicative, especially in the precordial leads, and often suggests the probable underlying
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genotype (FIG. 5). The exercise stress test almost never induces arrhythmias, at striking
variance with CPVT, but can provide three important pieces of information about QT
interval adaptation (or lack of it) to R–R interval shortening, T wave changes in the first
minutes of recovery161,162 — both useful parameters to support the diagnosis of LQTS —
and the rapidity of the reduction in heart rate during the first minute following cessation of
exercise163, which is important for risk stratification. The 24-h, 12-lead Holter ECG
recording provides almost invaluable information, especially about cardiac activity during
the night, because it is typical of LQTS to present even gross, albeit sudden and brief,
changes in T wave morphology. Finally, in several patients, there are specific mechanical
alterations, which can be identified by echocardiography164–169.
Since the late 1990s, genetic testing has not only aided the diagnosis of LQTS but has also
enabled the identification of the specific genotype and family members of patients who also
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carry the causative mutation (and are therefore at risk) but have a borderline QT interval
duration and would probably escape diagnosis and not receive protective measures. Of
course, the results of genetic tests must be interpreted correctly, and physicians who care for
these patients should know the difference between a disease-causing mutation and a variant
of uncertain significance170. Once the disease-causing mutation has been identified in the
proband, the entire family should undergo cascade genetic screening, which, within 2–3
weeks, can identify the relatives who are genotype-positive and those who are genotype-
negative68,69.
SQTS.—The hallmark of SQTS is a very short QT interval. SQTS was initially recognized
in patients with a QTc <300 ms. Subsequently, patients with slightly or moderately
shortened QT intervals (≤360 ms) and similar clinical presentations were also
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described47,142,171,172. Several population and cohort studies showed that the prevalence of
individuals with QTc <360 ms is very low. In a large Finnish cohort, the prevalence of
patients with a QTc <340 ms was 0.4%, and that of patients with a QTc <320 ms was
0.1%173. In a paediatric population, the prevalence of QTc ≤340 ms was 0.05%174. These
studies revealed that short QT interval alone was not associated with increased risk of
arrhythmic events. Thus, the cut-off value of QT interval for defining SQTS remains a
matter of debate, as there is an overlap between healthy individuals and patients with SQTS.
In the 2015 guidelines of the European Society of Cardiology175, a cut-off value of QTc
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≤340 ms was recommended for the diagnosis of SQTS (class I, level of evidence C). SQTS
should be also considered in patients with QTc ≤360 ms in the presence of one or more of
the following factors: a confirmed pathogenetic mutation; a family history of SQTS; a
family history of sudden death before 40 years of age; and non-fatal VT or ventricular
fibrillation episodes in the absence of structural heart disease (class IIa, level of evidence C).
Owing to the impaired QT adaptation to heart rate changes in patients with SQTS, experts
recommend measuring the QT interval on ECG with a heart rate between 50 and 70 beats
per min. Other prevalent ECG patterns that could be helpful in establishing the diagnosis of
SQTS include PQ segment deviation (observed in 81% of patients with SQTS), a pattern of
tall and symmetrical T waves with a very short or missing ST segment, early repolarization
(in 65% of patients with SQTS), frequent presence of apparent U waves (especially in
precordial leads) and impaired adaptation of the QT interval during exercise176–180.
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Furthermore, overlapping syndromes have been described in patients who had non-fatal
sudden cardiac arrest and presented with a BrS-like ECG pattern and a shorter than normal
QT interval. As in LQTS, genetic testing is recommended for patients with suspected SQTS.
However, similarly to BrS, a causative mutation is identified only in ~20% of cases and,
therefore, genetic test results must be interpreted very carefully.
CPVT.—In a child, adolescent or young adult with the clinical manifestation described
earlier, CPVT should always be considered. In CPVT, the heart is virtually always
structurally normal, and, in fact, identification of a structural abnormality should rule out a
CPVT diagnosis. Similarly, the 12-lead ECG at rest is essentially normal in CPVT99,181. The
diagnosis of CPVT is established in a clinically symptomatic patient who has a structurally
normal heart by cardiac imaging and a normal ECG at rest but an abnormal exercise stress
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test (FIG. 6). The appearance during exercise of bidirectional VT is regarded as

pathognomonic for CPVT. Although bidirectional VT provoked in this setting is extremely
specific for CPVT, it is seen only rarely.
The characteristic stress test profile of most patients with CPVT involves normal sinus
rhythm at rest, with the onset of single ventricular extrasystoles (PVCs) starting when the
sinus heart rate reaches ~110–130 beats per minute. As the heart rate increases, the single
PVCs (which often originate from the RVOT) increase in frequency and then progress to
PVCs in bigeminy. Next, the bigeminal pattern gives way to PVC couplets, including
bidirectional couplets, and then occasionally non-sustained VT, polymorphic VT and, rarely,
bidirectional VT at higher heart rates. Sometimes, the arrhythmic pattern that manifests
during exercise often ceases at the highest heart rates, and normal sinus rhythm then persists
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throughout the recovery phase, or, if arrhythmia persisted at the highest heart rates, the
arrhythmia ceases almost immediately in the recovery phase. Accordingly, in the patient
with a history consistent with CPVT and normal echocardiography and ECG, the presence
of exercise-induced arrhythmia in the pattern described that culminates in bidirectional PVC
couplets means that the diagnosis of CPVT is very likely to be correct, even though
bidirectional VT did not occur.
In a patient with suspected CPVT on the basis of clinical manifestations and cardiological
testing, CPVT genetic testing is indicated22. The vast majority of CPVT cases stem from
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pathogenetic missense variants in RYR2, and a rare missense variant can be identified in 60–
70% of patients with a robust clinical diagnosis of CPVT52. Of note, a rare missense variant
in RYR2 can also be found in 3% of healthy, asymptomatic individuals52. In other words,
when the clinical evidence for a CPVT diagnosis is compelling, identification of a rare
missense variant in RYR2 has at least a 20:1 chance of being the pathogenetic mutation of
CPVT type 1. In accordance with the 2013 HRS/EHRA/APHRS guidelines, the
identification of a CPVT type 1 causative mutation is deemed equivalent to a clinical
diagnosis of CPVT that should compel cascade, variant-specific genetic testing of all
appropriate relatives and the possible initiation of prophylactic β-adrenergic receptor blocker
therapy even in asymptomatic family members with a normal stress test who are positive for
the variant9.
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BrS.—BrS is diagnosed in the presence of a characteristic ECG pattern including a

spontaneous type 1 pattern with a coved ST segment elevation in one or both of the right
precordial leads V1 and V2, positioned in the second, third or fourth intercostal space17. A
type 1 ECG is mandatory for the diagnosis; only when a type 2 or type 3 ECG converts into
a type 1 pattern (that is, with a drug test) can the diagnosis of BrS be made. As described
earlier, type 1 morphology reflects a coved-type ST elevation of ≥2 mm (0.2 mV) in the
right precordial leads followed by a negative terminal ST segment182 (FIG. 5). In the
absence of a spontaneous abnormal ECG with the V1 and V2 leads in the standard positions,
the diagnostic sensitivity of the ECG can be increased by placing the right precordial leads
higher, administering a sodium channel blocker (the drug challenge test, with ajmaline being
the most effective drug, although the sensitivity and specificity of these tests is unknown) or
increasing the vagal tone (that is, by recording the ECG after the patient has had a meal or
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exercised)183. These procedures (preferably a drug challenge test or, alternatively, a ‘heavy
meal test’ or exercise test) should be performed in any patient with a reasonable suspicion of
BrS with a non-diagnostic baseline ECG. Additional clinical criteria are required to reach
the diagnosis in cases in which a type 1 ECG is only observed after drug challenge test or
during fever17, and a 12-lead 24-h Holter ECG recording performed at regular intervals can
be useful. Of note, several differential diagnoses are possible even when the ECG shows the
typical type 1 form184.
Management
Pharmacological therapy
LQTS.—The pharmacological therapy of LQTS is rather straightforward. With very few
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exceptions (see below), β-adrenergic receptor blockers should be given to every diagnosed
patient, because the risk of a fatal first event is high. The only two β-adrenergic receptor
blockers that are effective beyond doubt are propranolol and nadolol124. Metoprolol should
not be used185, as it is not effective; concerns about efficacy exist also for atenolol186, and
available data about the other β-adrenergic receptor blockers are insufficient. There is no
justification to risk the patients’ lives with drugs of uncertain efficacy. The few patients in
whom not starting β-adrenergic receptor blocker therapy may be considered are
asymptomatic males with LQT1 off therapy by 25 years of age122 and genotype-positive but
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phenotype-negative (that is, with a normal QTc) individuals. Incorrect considerations have
led for several years to the misconception that β-adrenergic receptor blockers would not be
useful, and potentially dangerous, for patients with LQT3; it is now evident that these drugs
are very effective also for these patients135,187.
The understanding of the mechanism of action of SCN5A mutations has led to the proposal
of using the sodium channel blocker mexiletine to shorten the QT interval in patients with
LQT3 (REF.188). This first example of gene-specific therapy was successful and was
confirmed by recent studies189. Whenever mexiletine shortens the QTc by >40 ms in
patients with a baseline QTc >500 ms, this drug should be added to therapy as recommended
in 2005 (REF.190) and also by the HRS/EHRA/APHRS guidelines9. Very recently, groups in
the Mayo Clinic and Milan have observed that mexiletine effectively shortens QTc also in a
small series of patients with LQT2, and this assessment has now become routine in these
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two large referral centres191. A practical point to be kept in mind is the simplicity and
rapidity by which it is possible to determine whether or not mexiletine is effective in a
patient, even without knowing the functional characteristics of the mutation that the patient
carries. Indeed, the therapeutic plasma concentration is reached within 90–120 minutes from
administration of half of the daily oral dose, and, by monitoring the ECG for 2 hours, it is
evident whether or not QTc shortens by at least 40 ms; if the QTc does shorten, the patient is
considered a responder, and mexiletine can be added to the therapeutic regimen. Despite
high hopes, there are insufficient data about the efficacy of ranolazine and other new sodium
channel blockers to recommend their use.
Finally, data on patient-specific iPS-CMs raise the possibility that the lumacaftor–ivacaftor
combination (a drug that corrects trafficking defects and is used clinically for cystic fibrosis)
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might be useful in patients with LQT2 with mutations causing trafficking defects192. Indeed,
the initial clinical data in the same patients whose iPS-CMs responded to lumacaftor seem to
support the experimental observation193.
SQTS.—The main predictor for recurrent arrhythmic events in patients with SQTS is a non-
fatal cardiac arrest event. Asymptomatic patients with QTc 300–360 ms should be monitored
and followed up without any prophylactic medication194. Patients with markedly shortened
QTc (≤300 ms) may be at increased risk of SCD, especially during sleep or rest. The only
pharmacological therapy that leads to lengthening of the QTc and reduction of arrhythmic
events is quinidine. Quinidine should be considered on a case-by-case basis in patients with
increased risk of SCD and strong family history of SCD as a primary prevention (class IIb,
level of evidence C)175. In patients with SQTS and recurrent ICD shocks, quinidine has been
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shown to prevent further ICD discharges142. Finally, emergency isoprenaline infusion can be
effective in patients with an electrical storm or refractory ventricular fibrillation to restore
and maintain sinus rhythm164.
CPVT.—β-Adrenergic receptor blocker therapy is the standard, first-line therapy in all

patients with symptomatic CPVT who manifested self-limiting syncope or seizures as their
sentinel event9,194. Nadolol is the preferred β-adrenergic receptor blocker in CPVT195,196.
Preliminary evidence suggests that carvedilol may be a suitable alternative, but only if
nadolol is either not available or not tolerated197. Combination drug therapy with a β-
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adrenergic receptor blocker and flecainide is increasingly utilized. In addition to its sodium
channel blocker activity, flecainide may help to reduce diastolic calcium SR overload by
stabilizing the ‘leaky’ RYR2s that stem from RYR2 defects198,199. A small, randomized,
placebo-controlled trial confirmed the ability of flecainide to decrease the burden of
exercise-triggered ventricular ectopy and arrhythmias200.
In general, among the largest CPVT centres throughout the world, the proxy to therapeutic
success is the normalization of the patient’s stress test, with general tolerance for the
occasional presence of PVCs in bigeminy that persist on therapy. If bidirectional PVC
couplets or worse arrhythmias persist during follow-up stress testing, medication doses are
increased, combination drug therapy is initiated201 or additional non-pharmacological
therapies are considered.
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BrS.—The options for pharmacological therapy are limited in BrS. Antiarrhythmic drugs
can be life-saving in the acute phase of an arrhythmic storm. Intravenous isoprenaline is the
most effective treatment, with an immediate effect on the arrhythmia burden and the ECG
pattern, which may normalize. The drug that has received the greatest interest so far and on
which multiple retrospective studies have yielded encouraging reports is quinidine202.
Cilostazol and milrinone (inotropic agents) are other drugs with reported beneficial effects in
some patients with BrS with arrhythmias17. Importantly, there is a long list of drugs that
have to be avoided in patients with BrS203 (Brugadadrugs.org), including virtually all
cardiac sodium channel blockers except quinidine.
Non-pharmacological therapy
LQTS.—Left cardiac sympathetic denervation (LCSD) and ICD are the two established
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non-pharmacological therapies that are the pillars for the management of LQTS, and genetic
progress has enabled gene-specific management. Family members of patients with LQTS
should receive cardiopulmonary resuscitation training, and, in particular, they should be
taught the importance of precordial thump, as this manoeuvre, if correctly performed within
1 minute from the onset of loss of consciousness, almost invariably restores sinus rhythm.
For children with LQTS, the acquisition of an automatic external defibrillator may be
considered204.
Since the early 1970s, patients in whom β-adrenergic receptor blockers are not sufficient to
prevent arrhythmic events have benefited from LCSD123,205–207. The rationale for this
surgical intervention is well under-stood208 and largely hinges on the interruption of the
release of noradrenaline from the left cardiac sympathetic nerves, which are quantitatively
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dominant at the ventricular level, and on the increase in the ventricular fibrillation threshold,
which means that it is more difficult for a VT to degenerate into ventricular fibrillation209.
As LCSD is a preganglionic denervation, there is no reinnervation or postdenervation
supersensitivity210. The currently preferred surgical approach is by thoracoscopy124,211–213,
which is simpler and less invasive than the traditional retropleural approach214. As LCSD
has few to no contraindications, it is performed increasingly often. The main indication
remains for patients not protected by β-adrenergic receptor blockers; however, LCSD is also
indicated in primary prevention when a patient, albeit asymptomatic on β-adrenergic

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receptor blockers, keeps showing signs of high risk, such as a QTc >500 ms or T wave
alternans207. LCSD is also effective in preventing multiple shocks in patients with an ICD207
and in low-risk patients who are intolerant to β-adrenergic receptor blockers. In the few
cases of LCSD failure, it is recommended to proceed with right cardiac sympathetic
denervation to obtain a complete bilateral sympathectomy. This sequential approach has
been used with success since the late 1980s206,207. There is no justification for performing a
bilateral cardiac sympathectomy in patients with LQTS or CPVT without having first
assessed whether unilateral LCSD has failed; otherwise, the patients would undergo a longer
and unnecessary surgery, doubling the risk of complications, and would be deprived without
reason of an important component of the adrenergic control of their cardiac function.
Importantly, the most common reason for post-LCSD breakthrough events is a suboptimal
surgical procedure whereby only the left stellate ganglion is removed100,207. Indeed, to be
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effective, LCSD requires section of the lower half of the left stellate ganglion together with
the first four thoracic ganglia208.
As a general rule, an ICD should be implanted whenever a patient has survived a cardiac
arrest. However, as per the 2013 guidelines9, after a careful assessment, young patients with
LQT1 who experienced a cardiac arrest while not on β-adrenergic receptor blocker therapy
could be treated only with β-adrenergic receptor blockers and/or LCSD215. In all other
patients, the pros and cons of ICDs should be very carefully considered, and the alternative
option of LCSD should always be presented to the patients and their families216,217. The
largest study on ICDs in LQTS has shown that a staggering 31% of patients have adverse
events (for example, infection, lead dislodgement and tricuspid valve insufficiency) within 5
years from the implant, and the younger the patient, the higher the number of ICD
substitutions that will be required over time218. A correct strategy is often to use both
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approaches — LCSD to prevent arrhythmic episodes and the ICD as a safety net.
Finally, the understanding of gene-specific triggers for arrhythmic events has led to gene-
specific management for LQTS190. Patients with LQT1 should limit exposure to physical
and, if possible, emotional stress; they should be allowed to swim but under the supervision
of an adult who can swim. Their sport participation is questionable, depends on the local
laws, and different views coexist219–222. Patients with LQT2 are at risk especially when
exposed to sudden noises when they are at rest or asleep; alarm clocks and telephones
should be avoided in their bedrooms. These individuals are also very sensitive to decreases
in their plasma potassium levels. Potassium supplements should be given after repeated
episodes of diarrhoea and potassium-sparing agents to patients with chronically low
potassium levels. Women with LQT2 are at increased risk in the postpartum period and
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should avoid sleep deprivation, if at all possible. Their partners should take care of feeding
the infant during the night-time, when breast-feeding can be avoided. The indications for
patients with LQT3 are more uncertain, as arrhythmic events in these patients tend to occur
at night. As night-time deaths in both LQT2 and LQT3 are often not silent223, it is
recommended to have an intercom in the room if the patient is a child, and that adults sleep
with another adult, as these measures would enable recognition of gasping noises and
prompt intervention.
SQTS.—Patients with SQTS with a history of cardiac arrest or with documented

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spontaneous sustained VT are at increased risk of recurrent arrhythmic events (with an

estimated risk of recurrent cardiac arrest of 10% per year) and, therefore, should receive an
ICD for secondary prevention. Quinidine is recommended to reduce the number of ICD
shocks. In patients who refuse ICD implantation, treatment with quinidine may be
considered9,176.
CPVT.—The most rational and recommended non-pharmacological therapeutic option for

CPVT is videoscopic LCSD surgery100,211,224. The LCSD surgical procedure is the same
previously reported for LQTS. LCSD is indicated as a treatment intensification option for
patients with recurrent sustained VT during stress testing or recurrent syncope despite
receiving adequate or maximally tolerated β-adrenergic receptor blocker therapy194 or
combination therapy.
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The other option is the placement of an ICD. Because CPVT has a higher lethality per
cardiac event than LQTS, the management of both symptomatic and asymptomatic patients
with CPVT tends to be more aggressive, with increased ICD use. However, CPVT is the
only entity in which ICD itself may contribute to not only morbidity but also
mortality225–227. Indeed, ICD-associated comorbidities are far more severe than those of
either pharmacological therapy or LCSD, and inappropriate shocks are an inherent painful
and stressful experience that may elicit a lethal arrhythmic storm. In such situations, an
initial inciting shock occurs inappropriately owing to sinus tachycardia or atrial fibrillation
and activates the CPVT substrate, thereby precipitating a severe and ultimately fatal
electrical storm225–227. The most recent analysis of the effect of ICD implants in patients
with CPVT has concluded that ICD use should be limited as much as possible and LCSD
should be favoured228. Presently, the largest and more experienced CPVT centres throughout
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the world increasingly aim to reserve ICD only for patients with CPVT with a clinical
manifestation of sudden cardiac arrest that required external defibrillation resuscitation.
However, even in these centres, if the sentinel event of sudden cardiac arrest occurred while
the individual was undiagnosed and, therefore, untreated, it may still be possible to
successfully implement a non-ICD treatment programme with triple therapy (nadolol,
flecainide and LCSD) that may confer the same survival benefit as an ICD but without its
comorbidities.
BrS.—Non-pharmacological therapy options consist of ICD implant and, more recently,

epicardial ablation of the arrhythmogenic substrate (that is, areas that generate fractionated
ECG) in the RVOT area. Patients who have survived a cardiac arrest or who have
demonstrated ventricular arrhythmias have a class I indication for an ICD implant9.
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Epicardial ablation of the RVOT was first performed in nine severely symptomatic patients;
after ablation of an area with abnormal low amplitude QRS voltages and late to very late
(>200 ms) fractionated activity, in eight patients the ECG normalized, and recurrence of
arrhythmic events was successfully prevented229. This epicardial approach was investigated
in a larger cohort, which also included asymptomatic patients; the ECG manifestations
disappeared after the procedure and could no longer be elicited by ajmaline or flecainide
exposure, and in the 39 symptomatic patients no arrhythmia recurred in the short (10
months) follow-up period230. The exact role for epicardial ablation has to be established; of
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note, given the potential complications of this procedure (for example, tamponade or
damage to the coronary arteries) and the relatively low event rate in asymptomatic patients
with BrS with a type 1 ECG, a prophylactic epicardial ablation in asymptomatic patients
raises major ethical questions and should be discouraged at present231.
Pregnancy-associated risk
This section focuses primarily on LQTS, as this channelopathy is the only one with adequate
studies during pregnancy. The only study in CPVT to date indicates no augmented maternal
risk during or after pregnancy232. Similarly, arrhythmic event rates in women with BrS do
not seem to be elevated during pregancy233; thus, the management of BrS in pregnancy is
limited to aggressive fever management and avoidance of medications that may provoke
arrhythmias.
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Maternal risk of adverse events.—Surveillance during pregnancy in women with

channelopathies focuses on primary arrhythmia prevention with adequate β-adrenergic
receptor blockade, monitoring for breakthrough arrhythmias and identification of high-risk
women (that is, those with a history of syncope or cardiac arrest). There are abundant data
supporting the safety of commonly used β-adrenergic receptor blockers in
pregnancy134,234,235. The β-adrenergic receptor blockers with proven efficacy in LQTS are
nadolol and propranolol. Atenolol should not be used in pregnancy, as it is associated with
significant intrauterine growth restriction (pregnancy class D)236. The genetic subtype is also
an important modulator of pregnancy-related arrhythmia risk. Postpartum cardiac event rates
are <1% in LQT1 but reach 16% in patients with LQT2 (REF.133), and this observation
mandates specific cautionary measures as described; there are no data for LQT3 (REF.133).
Recent studies have also shown that the risks of miscarriage and stillbirth are increased in
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LQTS pregnancies, and the probability of fetal death is greater if the mother, rather than the
father, carries the pathogenetic mutation (or mutations) (24.4% and 3.4%, respectively)237.
Labour and delivery management.—The management plan for labour and delivery
should be individualized. Low-risk women (with no previous arrhythmic events) who are
adequately treated with β-adrenergic receptor blockers can safely proceed with spontaneous
vaginal delivery unless there are maternal or fetal indications for assisted or Caesarean
delivery. Although active pushing increases the maximal heart rate, the heart rate response is
expected to be blunted in a woman with adequate β-adrenergic receptor blockade. In
pregnant women with LQTS, intrapartum rhythm monitoring is not necessary, as event rates
are extremely low. However, cardiac tele metry is advisable during labour in women with
CPVT, as arrhythmia can occur and progress from isolated PVCs to more complex and
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unstable ventricular arrhythmias. Caesarean delivery with maternal telemetry should be

considered in pregnant women with poorly controlled arrhythmias or a history of cardiac
arrest238.
Any pharmacological therapy in women with LQTS or BrS should be reviewed239.

Oxytocin, commonly used during labour and delivery, has some potential for QT
prolongation240, but this effect should not preclude the use of oxytocin when indicated241. A
reasonable approach to oxytocin use is to optimize serum potassium and magnesium levels
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and to obtain an ECG at baseline and 1–2 h after oxytocin is initiated. The drug should be
discontinued if the QTc exceeds 500 ms or increases beyond 60 ms from baseline86.
Decisions regarding analgesia, including neuronal axial blockade, should be made according
to maternal preference and estimated obstetric risk.
Management of the newborn baby.—Neonatal genetic screening for the familial

pathogenetic variant should be performed. Because the QT interval is often prolonged in
healthy newborn babies for the first 7–10 days242,243, 12-lead ECG screening of the neonate
who is at risk of LQTS is unreliable for the diagnosis of LQTS until after the second week
of life10, unless QTc of the newborn baby exceeds 500 ms. The Bazett method to calculate
QTc is valid and useful also in infants244. Until the genetic test results are available, or if a
variant of unknown significance is detected, ongoing clinical follow-up is recommended.
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Pregnancy and risk of disease transmission.—When one of the parents is affected

by a channelopathy and the disease-causing mutation is known, the cardiologist is often
asked whether it is possible to prevent transmission of this potentially life-threatening
disorder to the offspring. The cardiologist has the responsibility of providing the essential
information on in vitro fertilization and pre-implantation genetic screening of the embryo, as
this approach allows the possibility of favouring the development of the embryo without the
mutation, thereby ensuring the offspring will not have the disease present in the
family245–247.
Quality of life
The quality of life of the patients should be a primary concern for their doctors. For
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channelopathies, there are three main aspects to consider: the negative effects of certain
therapies (mainly ICDs), the effect on sports participation and the specific concerns of
patients with BrS.
ICDs are undoubtedly life-saving devices but, in these disorders, when physicians opt for an
ICD they might be influenced to some extent by their own wish to avoid possible negligence
investigations. ICDs often have a very negative effect on the quality of life, especially in
young patients. In particular, patients with LQTS or CPVT are very sensitive to
catecholamines, and the pain and fear generated by every ICD shock often contribute to
initiate a vicious cycle of recurrent VT and/or ventricular fibrillation, which can result in an
electrical storm with multiple ICD shocks. Experienced investigators limit the use of ICDs
as much as possible in these patients124, and, barring a previous cardiac arrest, whenever
feasible they use LCSD instead. Indeed, LCSD has been associated with a documented
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improvement in quality of life248,249.
For a youngster involved in competitive sports, having to stop practising following the
diagnosis of a channelopathy is a major negative event with substantial psychological
effects. Physician recommendation on whether it is appropriate to continue the sporting
activity should take into account the local legislature (as in some regions the law forbids
competitive sports for individuals with these diseases), the type of sports and the specific
characteristics of the individual patient250. Owing to the pressure to perform by the other
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players, team sports are more dangerous than individual sports in which players may decide
how much to push themselves. Phenotypic and genotypic features should also be considered
(for example, patients with LQT2 or LQT3 are at somewhat lower risk than individuals with
LQT1). The European Society of Cardiology is updating its previous consensus
document251, which provided different perspectives compared with the more recent and
more liberal consensus document by the American Heart Association and the American
College of Cardiology250.
Asymptomatic patients with BrS and a spontaneous type 1 ECG have a unique problem, as
they are usually told that their major risk is to die suddenly at night, and their options are
limited to implanting an ICD, which would potentially be used in ~1% of them yearly,
whereas the others would remain without cardiac events. Such a situation causes anxiety in
these patients and their families. Thus, the mildly encouraging data with quinidine are
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welcome, as they enable doctors to encourage and reassure patients. A future therapeutic
option could be prophylactic ablation of the RVOT area with abnormal QRS complexes.
However, a multicentre randomized trial to demonstrate that the benefits out-weigh the
complication rate of the ablation procedure in patients who are still asymptomatic is
mandatory before this procedure enters regular clinical practice.
Outlook
LQTS
The current approach to LQTS management is overall very satisfactory, and sudden death
among properly treated patients is rare nowadays, with the exception of infants presenting
with cardiac events in the first year of life because of their poor response to therapy.
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However, too many patients who would benefit from LCSD do not receive it, as even in
large centres there are few surgeons capable of performing LCSD or else this option is not
offered to the patient. This same problem occurs in CPVT.
Two areas of ongoing active research have the potential of providing a very useful clinical
fallout and, therefore, should be expanded. One is the field investigating genetic modifiers71,
as increased knowledge of these factors could help to improve risk stratification, and
understanding their mechanisms of action72 might lead to novel therapies. The second area
involves the use of patient-specific iPS-CMs, as recent data193,252 raise the possibility that
they might represent a useful tool to identify drugs that are effective against mutation-
specific arrhythmogenic mechanisms.
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SQTS
Patients with SQTS are very rare, as <200 cases have been reported; accordingly, data on
risk stratification are lacking. The European Short QT registry should be expanded to better
understand the natural course of this disease. Furthermore, we have only limited information
on overlap syndromes such as the combination of a shorter than normal QT and BrS. Data
on long-term treatment with quinidine are also lacking, and adherence to and tolerability of
quinidine therapy remain a problem. Perhaps in the future the use of iPS-CM research will
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help to identify effective patient-specific drugs that can restore the functions of ion channels.
CPVT
Numerous advances are needed in the diagnosis, prognosis and therapy of CPVT. In one-
third of individuals with a clinical diagnosis of CPVT, a pathogenetic defect cannot be
identified, suggesting that some CPVT-associated genes have not yet been identified. In
addition, long delays persist in the diagnosis of CPVT. In particular, young patients
presenting with a sentinel event of sudden cardiac arrest are often recommended ICD
implantation as a secondary prevention measure after completing a cardiological evaluation
to rule out both structural and arrhythmic causes of SCD. However, such evaluation often
fails to include an exercise stress test, thereby failing to test for possible CPVT. This must
change.
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The identification of patients who are at negligible risk remains difficult, and, therefore,
universal β-adrenergic receptor blocker therapy remains the general recommendation.
Nevertheless, treating all patients with CPVT with lifelong prophylactic β-adrenergic
receptor blocker therapy on the basis solely of a positive CPVT genetic test is wholly
unsatisfying, and much progress is needed in risk stratification. In addition, there is
substantial heterogeneity throughout the world in the treatment of patients with previously
symptomatic CPVT, ranging from β-adrenergic receptor blocker therapy only, to
combination drug therapy with β-adrenergic receptor blockers and flecainide, combination
therapy and LCSD, and ICD therapy only. We must increase awareness that, among these
options for symptomatic patients, β-adrenergic receptor blockade monotherapy is probably
insufficient and ICD monotherapy should never be recommended228. In the future, perhaps a
patient who presents with sudden cardiac arrest and is subsequently diagnosed with CPVT
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may be effectively treated with combination drug therapy and LCSD rather than with ICD.
Finally, regarding quality of life, continued observational studies are needed to determine
whether, akin to some cases of LQTS, sports participation in a well-treated patient with
CPVT might be a reasonable consideration.
BrS
BrS is probably one of the disease entities with the most controversial issues and open
questions. The most pressing questions concern the pathogenesis (including the role of
genetics), risk stratification and the best treatment options. Thus, future research should be
directed towards these areas. Large patient registries, with detailed clinical data, will be
needed to ultimately identify the clinical parameters that contribute to risk and to quantify
the risk of individual patients, in particular asymptomatic patients. To date, conflicting data
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exist on most proposed risk factors157, and a pooled analysis of all BrS registries may be the
way forwards. When combined with genetic data, such analysis could also identify genetic
factors that contribute to risk stratification. The presence of more than four (out of six) risk
alleles, identified through genome-wide association studies, is more likely to result in a type
1 ECG pattern67. This dataset is currently being expanded, and, in a much larger set of
patients, additional risk alleles might be identified and more statistical power might be
present to successfully associate the number of risk alleles with the risk of cardiac events.
Finally, the role of targeted epicardial ablation should be studied through multicentre
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randomized trials before individual centres start performing epicardial ablation of RVOT in
asymptomatic patients. Invasive ablation procedures should be performed by very
experienced clinicians in high-capacity centres and should also be used to gain more insight
into the electrophysiological mechanisms of the ECG characteristics. Specific pacing
protocols may be one way to provide this much needed insight.
Acknowledgements
The authors thank P. De Tomasi (Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic
Origin, Milan, Italy) for an extraordinary editorial support. C.A. acknowledges support from NHLBI (HL47678,
HL138103 and HL152201), the W.W. Smith Charitable Trust and the Martha and Wistar Morris Fund; C.R.B.,
P.J.S. and A.A.M.W. acknowledge the support of ERN GUARD-Heart; C.R.B. and A.A.M.W. acknowledge the
support of the Netherlands Heart Foundation (CVON Predict2 project) and Leducq Foundation for Cardiovascular
Research grant 17CVD02 “The sodium channel as a therapeutic target for prevention of lethal cardiac arrhythmias”;
P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05 “Towards
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Precision Medicine with Human iPSCs for Cardiac Channelopathies” and of ESCAPE-NET project (European
Union’s Framework Horizon 2020 programme under grant agreement no. 733381). M.B. acknowledges support
from the German Center for Cardiovascular Research (DZHK) and Hector Foundation. M.J.A. acknowledges
support from the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.
Glossary
U wave
A small deflection immediately following the T wave and usually in the same direction.
Polymorphic ventricular tachycardia

Rapid ventricular rhythm with a continuously varying QRS complex morphology.
Refractoriness
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Also known as refractory period. The period of depolarization and repolarization of the cell
membrane after excitation during which the cell cannot respond to a second electrical
stimulus.
Reentry
A self-sustaining rhythm abnormality that occurs when the propagating electric impulse fails
to conclude and the action potential propagates in a closed loop manner.
Torsades de Pointes
A specific form of polymorphic ventricular tachycardia characterized by a gradual change in
the amplitude and twisting of the QRS complexes around the isoelectric line.
Conduction velocity
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The speed at which an action potential is distributed throughout the myocardium; conduction
velocity is still the primary metric for quantifying the spread of electrical activity in cardiac
muscle.
Transmural dispersion of repolarization

The difference between the longest and the shortest repolarization times measured at two
points across the cardiac wall.
Early afterdepolarization
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Spontaneous diastolic depolarization that occurs during phase 2 and/or phase 3 of the
cardiac action potential, thereby delaying repolarization.
Triggered activity
The generation of spontaneous action potentials outside the sinus node as a result of
afterdepolarizations.
Focal activity
Abnormal formation of a depolarizing impulse outside the sinus node.
Wavelength
The distance travelled by the excitation wave during its refractory period.
Delayed afterdepolarizations
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Spontaneous diastolic depolarizations that occur after repolarization is complete.
Bidirectional VT
A ventricular tachycardia (VT) in which the QRS axis (as seen in the frontal
electrocardiogram leads) shifts 180° with each alternate beat.
J waves
Dome-like deflections of the electrocardiogram trace between the QRS complex and the ST
segment.
Right ventricular outflow tract

(RVOT). an extension of the infundibulum (a conical pouch of the right ventricle) in the
ventricular cavity through which the blood flows towards the pulmonary artery.
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T wave alternans
Beat-to-beat variation in the polarity or amplitude of T waves; this phenomenon indicates an
unevenness in the refractoriness of the myocardium and points to elevated cardiac electrical
instability.
Electrical axis
The net direction of the depolarization activity, resulting from the sum of all the electrical
vectors on ECG.
Bigeminy
Heart rhythm characterized by two beats close together with a pause following each pair of
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beats; the first beat in the pair is the sinus beat, whereas the second one is a premature
contraction. bigeminy rhythm is often associated with the sensation of the heart skipping a
beat.
PVC couplets
Two premature ventricular contractions (PVCs) in consecutive heart beats.
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ventricle. Circ. Res 72, 671–687 (1993). [PubMed: 8431990]

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RElatED links
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Brugadadrugs.org: www.brugadadrugs.org
European Reference Network for rare and Low Prevalence Complex Diseases of the
Heart (ERN GUARD-HEART): http://guardheart.ern-net.eu
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Box 1 |
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1993–2011 long QT syndrome diagnostic criteria

ECG findings
Electrocardiogram (ECG) findings can be included in the score in the absence of
medications or disorders known to affect ECG features. Corrected QT (QTc) is calculated
by Bazett’s formula, in which QTc = QT/√RR.
• QTc 450–459 ms (in male individuals) (1 point)
• QTc 460–479 ms (2 points)
• QTc ≥480 ms (3 points)
• QTc on fourth minute of recovery from exercise stress test ≥480 ms (1 point)
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• Torsades de Pointes (2 points)
• T wave alternans (1 point)
• Notched T wave in three leads (1 point)
• Resting heart rate below the second percentile for the patient’s age (0.5 point)
Clinical history
• Syncopea with stress (2 points)
• Syncopea without stress (1 point)
• Congenital deafness (0.5 point)

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Family history
• Family members with definite long QT syndrome (LQTS) diagnosisb (1

point)
• Unexplained sudden cardiac death before 30 years of age among first-degree

relativesb (0.5 point)
A score of ≤1 point indicates a low probability of LQTS, a score of 1.5–3 points indicates
an intermediate probability of LQTS, and a score of ≥3.5 points indicates a high
probability of LQTS.
aMutually exclusive. bMutually exclusive. Adapted from REF.160, Schwartz P. J. & Crotti
L. QTc behavior during exercise and genetic testing for the long-QT syndrome.
Circulation 124(20), 2181–2184 (https://www.ahajournals.org/journal/circ).
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Fig. 1 |. Genes and proteins involved in the pathogenesis of inherited cardiac arrhythmias.
The figure shows the transmembrane ionic channels that are responsible for the potassium
(IKs, IK1 and IKr), calcium (ICa) and sodium (INa) currents that contribute to the cardiac
action potential. Proteins of the sarcoplasmic reticulum that are involved in calcium handling
(encoded by CASQ2, RYR2, CALM1, CALM2, CALM3 and TRDN) are also shown. Other
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proteins that can be mutant in inherited cardiac arrhythmias are encoded by ANK2 and
TECRL. The genes that encode all these proteins or their subunits are coloured according to
the disease with which they have been associated. BrS, Brugada syndrome; CPVT,
catecholaminergic polymorphic ventricular tachycardia; LQTS, long QT syndrome; SQTS,
short QT syndrome.
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Fig. 2 |. Variability in baseline QTc.

Distribution of the duration of heart rate corrected QT interval (QTc) in individuals who
carry the same KCNQ1 mutation and who belong to a LQT1 South African founder
population. The vertical dashed line represents the upper limit of normal values for men
(440 ms). If the QTc prolongation were determined only by the A341V mutation, the QTc
values should be uniformly prolonged with modest variability. The large spectrum of QTc
values points to the presence of additional variants affecting ventricular repolarization. Data
from REF.12.
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Fig. 3 |. Ventricular action potential and ionic currents.

a | Schematic showing a normal electrocardiogram trace and the corresponding phases of the
ventricular action potential (0, 1, 2, 3 and 4) that determine the shape of the trace. b | The
major transmembrane ionic currents that generate the ventricular action potential. Inward
currents that contribute to depolarization are oriented downwards, and outward currents that
contribute to repolarization are oriented upwards; the shapes of the currents indicate their
relative intensity. Ito, transient outward potassium current.
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Fig. 4 |. Spatial dispersion of repolarization.

a | A prominent transient outward current (Ito) is responsible for phase 1 of the action
potential (AP), giving rise to a prominent AP notch in the epicardium but not in the
endocardium, where this current is relatively small. b | The presence of a prominent notch in
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the epicardium but not the endocardium gives rise to a transmembrane voltage gradient.
Heterogeneous transmural distribution of the Ito-mediated AP notch is responsible for the
inscription of the J wave on the electrocardiogram (ECG). Part a adapted from REF.253, Liu,
D. W., Gintant, G. A. & Antzelevitch, C. Ionic bases for electrophysiological distinctions
among epicardial, midmyocardial, and endocardial myocytes from the free wall of the
canine left ventricle. Circ. Res. 72(3), 671–687 (https://www.ahajournals.org/journal/res).
Part b adapted from REF.108, Yan G. X. & Antzelevitch C. Cellular basis for the
electrocardiographic J wave. Circulation 93(2), 372–379 (https://www.ahajournals.org/
journal/circ).
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Fig. 5 |. Examples of ECG traces.

a | Example of electrocardiogram (ECG) traces of patients with long QT syndrome (LQTS).
In LQTS type 1 (LQT1), the QT interval is extremely prolonged, with a tall peaked T wave.
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In LQT2, a very prolonged QT interval is present, with a clear and typical notch on the T
wave (arrow). In LQT3, a very prolonged QT interval is followed by a late-onset diphasic
(arrows) T wave. b | In a patient with short QT syndrome (SQTS), the QT interval is
extremely short, with a tall peaked T wave (arrow). c | A patient with Brugada syndrome
(BrS) has an ECG trace with a typical type 1 pattern. There is a coved-type ST segment
(arrow) in the right precordial leads followed by a terminal negative T wave (arrow).
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Fig. 6 |. Catecholaminergic polymorphic ventricular tachycardia exercise test.

Exercise stress test in a patient with catecholaminergic polymorphic ventricular tachycardia
as confirmed by genetic analysis. Sinus rhythm was normal at rest, with ectopy increasing
with exercise. The patient demonstrated single premature ventricular contractions (PVCs)
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(arrow) with increasing frequency as the heart rate (HR) progressively increased,
transitioning to PVCs in bigeminy (dotted circle in stage 3) with couplets (dotted circle in
stage 4) and triplets at peak exercise. Ectopy disappears after 5 min of recovery, and normal
sinus rhythm is restored. bpm, beats per minute.
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Table 1 |
Genes frequently associated with inherited cardiac arrhythmias
Gene Protein Function Associated disorder Inheritance

KCNQ1 Potassium voltage-gated channel subfamily KQT Subunit of the voltage-gated potassium channel responsible for the IKs LQTS (LQT1) AD
Schwartz et al.
member 1 (also known as KV7.1) current

Jervell and Lange-Nielsen AR
syndrome
SQTS (SQT2) AD
KCNH2 Potassium voltage-gated channel subfamily H member 2 Pore-forming subunit of the voltage-gated potassium channel LQTS (LQT2) and SQTS AD
(also known as KV11.1) responsible for the IKr current (SQT1)
KCNE1 Potassium voltage-gated channel subfamily E member 1 Subunit of the potassium channel responsible for the IKs current Jervell and Lange-Nielsen AR
syndrome
KCNJ2 Inward rectifier potassium channel 2 (Kir2.1) Potassium channel responsible for the IK1 current Andersen–Tawil syndrome AD
and SQTS (SQT3)
SCN5A Sodium channel protein type 5 subunit-α (also known as Subunit of the voltage-gated sodium channel responsible for the INa LQTS (LQT3) AD
NaV1.5) current
BrS Complex
inheritance
CALM1 Calmodulin 1 Calcium-binding protein LQTS and CPVT AD
CALM2 Calmodulin 2 Calcium-binding protein LQTS and CPVT AD
CALM3 Calmodulin 3 Calcium-binding protein LQTS AD
ANK2 Ankyrin B Protein involved in the localization and membrane stabilization of ion CPVT AD
transporters and ion channels
TRDN Triadin Sarcoplasmic reticulum component of the calcium release unit LQTS and CPVT AR
CACNA1C Voltage-dependent L-type calcium channel subunit α1C Pore-forming subunit of the calcium channel responsible for L-type Timothy syndrome AD
(also known as CaV1.2) calcium currents
RYR2 Ryanodine receptor 2 Sarcoplasmic reticulum calcium channel CPVT AD

CASQ2 Calsequestrin 2 Component of the sarcoplasmic reticulum calcium release unit CPVT AR
TECRL Trans-2,3-enoyl-CoA reductase-like Endoplasmic reticulum protein CPVT AR
AD, autosomal dominant; AR, autosomal recessive; BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; LQT1, type 1 long QT syndrome; LQTS, long QT syndrome;
SQT1, type 1 short QT syndrome; SQTS, short QT syndrome.
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Inherited cardiac arrhythmias

3Department of Cardiovascular Medicine/Division of Heart Rhythm Services, Mayo Clinic,

blockers (such as quinidine), or surgical interventions, including left cardiac sympathetic

Following a brief overview of epidemiology, genetics and underlying electrophysiological

concerning ethnic differences in the prevalence of these arrhythmias is limited, as most of

Genotype–phenotype correlations.—Genotype–phenotype studies in the KCNQ1 and

Other LQTS-associated genes.—Several other genes encoding either ion channel

Patients with LQTS harbouring variants in CALM1, CALM2 or CALM3 (encoding

calcium-sensing, signal-transducing protein that regulates many calcium-dependent

Extracardiac manifestations.—Three clinical variants of LQTS manifest with

Lange-Nielsen syndrome, characterized by sensori-neural deafness and high arrhythmic risk,

facial dysmorphism and hypokalaemic periodic paralysis, is caused by dominantly inherited

SQT3, respectively. In contrast to loss-of-function variants associated with LQTS, SQTS-

Pathophysiology of the individual arrhythmias

SDR as a common link in arrhythmogenesis.—The four channelopathies thus far

LQTS.—In LQTS80–82, a reduction of net repolarizing current secondary to loss of function

myocardium, secondary to exaggerated trans-septal or transmural dispersion of

SDR is further exaggerated by sympathetic influences, especially in LQT1 and LQT2,

SQTS.—SQTS is an extremely rare channelopathy, characterized by pathologically

CPVT.—Mutations in RYR2, calsequestrin 2 (a calcium-binding protein that acts as a

delayed afterdepolarizations. Several lines of evidence point to delayed afterdepolarization-

interaction with peptidyl-prolyl cis–trans isomerase (FKBP) proteins owing to

the transition of bidirectional VT to polymorphic VT and ventricular fibrillation in the

discussed below (by C.A.).

repolarization hypothesis, as does the demonstration of a lack of conduction delay in the

A.A.M.W.—In every debate on the pathophysiological substrate of the ST segment elevation

Diagnosis, screening and prevention

CPVT.—Phenotypically, CPVT most closely mimics LQT1, with adrenergic-triggered

near drowning, CPVT should be explored as a possibility. In addition, CPVT should be

Diagnosis) and malignant ventricular arrhythmias148,149, more specifically rapid

frequently affected than females, as shown by every study.

intensity protocol is used158.

test (FIG. 6). The appearance during exercise of bidirectional VT is regarded as

BrS.—BrS is diagnosed in the presence of a characteristic ECG pattern including a

CPVT.—β-Adrenergic receptor blocker therapy is the standard, first-line therapy in all

indicated in primary prevention when a patient, albeit asymptomatic on β-adrenergic

SQTS.—Patients with SQTS with a history of cardiac arrest or with documented

spontaneous sustained VT are at increased risk of recurrent arrhythmic events (with an

CPVT.—The most rational and recommended non-pharmacological therapeutic option for

BrS.—Non-pharmacological therapy options consist of ICD implant and, more recently,

Maternal risk of adverse events.—Surveillance during pregnancy in women with

unstable ventricular arrhythmias. Caesarean delivery with maternal telemetry should be

Any pharmacological therapy in women with LQTS or BrS should be reviewed239.

Management of the newborn baby.—Neonatal genetic screening for the familial

Pregnancy and risk of disease transmission.—When one of the parents is affected

improvement in quality of life248,249.

Polymorphic ventricular tachycardia

Transmural dispersion of repolarization

Spontaneous diastolic depolarizations that occur after repolarization is complete.

Right ventricular outflow tract

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