AACN Advanced Critical Care
Volume 29, Number 1, pp. 43-57
Cardiac Channelopathies:
Recognition, Treatment, Management
Kathleen T. Hickey, FNP-BC, ANP-BC, EdD
Amir Elzomor
ABSTRACT
The discovery of the human genome has
ushered in a new era of molecular testing,
advancing our knowledge and ability to iden-
tify cardiac channelopathies. Genetic varia-
tions can affect the opening and closing of the
potassium, sodium, and calcium channels,
resulting in arrhythmias and sudden death.
Cardiac arrhythmias caused by disorders of
ion channels are known as cardiac channelo-
pathies. Nurses are important members of
many interdisciplinary teams and must have
a general understanding of the pathophysiol-
ogy of the most commonly encountered
W ith advancements in molecular genet-
ics, our knowledge of common and
rare cardiac conditions has improved and a
new era of precision medicine has been ush-
ered in.1 However, despite the growth of our
knowledge of cardiovascular genomics con-
cepts, the application of genetic information
to improve personalized clinical outcomes
remains to be implemented fully in clinical
practice.2 With almost 3 million nurses work-
ing in the United States,3 nursing is indispens-
able in the roles of integrating health care
advancements, enhancing genomic literacy,
and increasing proficiency in recognizing
inherited cardiovascular conditions. Genomic
knowledge is fundamental to ensuring clinicians
recognize common and rare cardiac condi-
tions and have the necessary competencies to
understand and manage these conditions.4
Cardiac arrhythmias caused by disorders
of ion channels are known as cardiac chan-
nelopathies. These genetic variations can
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© 2018 AACN
cardiac channelopathies, electrocardiogram
characteristics, approaches to treatment, and
care for patients and their families. This article
provides an overview of cardiac channelopa-
thies that nurses might encounter in an array
of clinical and research settings, focusing on
the clinically relevant features of long QT
syndrome, short QT syndrome, Brugada
syndrome, catecholaminergic polymorphic
ventricular tachycardia, and arrhythmogenic
right ventricular dysplasia/cardiomyopathy.
Keywords: genetics, cardiac, channelopathy,
arrhythmia, sudden cardiac death
affect the opening and closing of the potas-
sium, sodium, and calcium channels, resulting
in ionic changes across the cardiac membrane
that may lead to arrhythmias and sudden
death.2 An understanding of the molecular
pathophysiology, electrocardiogram charac-
teristics, and clinical presentation can guide
nurses and other members of the interdisci-
plinary team in implementing an effective
plan of care.
Polygenic conditions such as diabetes, obe-
sity, heart disease, dyslipidemia, and stroke
Kathleen T. Hickey is Professor of Nursing, Columbia University
Medical Center, 622 W 168th St, New York, NY 10032
(kth6@cumc.columbia.edu).
Amir Elzomor is a premedical student at the Albert Dorman
Honors College at the New Jersey Institute of Technology,
Newark, New Jersey.
The authors declare no conflicts of interest.
DOI: http://doi.org/10.4037/aacnacc2018664
H I C K EY AN D E LZ O MOR
have complex traits (ie, multiple genes and
interactions that are influenced by behavioral
and environmental factors).2 Coronary artery
disease, the leading cause of death in the United
States,5 comprises a broad spectrum of clini-
cal entities, including myocardial infarction
and sudden cardiac death, and is associated
with a complex heterogeneity of gene and
environmental interactions.6 Although studies
have established genetic markers for prema-
ture coronary artery disease, hyperlipidemia,
and other polygenic conditions,7,8 the specific
degree of influence of an individual’s genetic
predisposition versus his or her lifestyle and
environment has been more difficult to estab-
lish.2 Inherited defects in the low-density lipo-
protein receptor can result in a genetic variation
in the apolipoprotein B gene, which can impair
the ability of cells to remove cholesterol-
carrying particles from the bloodstream, result-
ing in significant accumulation of cholesterol
in heart tissue, which can lead to premature
coronary artery disease.2,9,10 Along with the
genetic involvement, an individual’s environ-
ment, such as consuming a high-fat diet with
the absence of exercise, could be a contribut-
ing factor to premature coronary artery dis-
ease, which could influence the expression
of the phenotype.11
Knowledge of gene and environmental
influences is evolving and genetic testing and
screening for polygenic cardiovascular disor-
ders currently are not available in clinical prac-
tice. However, understanding of the numerous
monogenic disorders has grown, allowing for
a personalized precision approach to cardio-
vascular health.4 In particular, major advance-
ments have developed in understanding the
underpinnings of the monogenetic or single-
gene disorders (inherited channelopathies)
of the heart.
The heart beating is the result of a delicate
balance of sodium ions, potassium ions, and
calcium ions at the cellular level. Cardiac chan-
nelopathies can result from underlying genetic
abnormalities that cause the ion channels to
be dysfunctional, allowing too much or too
little sodium, potassium, or calcium to flow
across the cardiac membrane. Tragically, the
initial presentation of an underlying inherited
arrhythmia can be sudden cardiac death.
This article provides nurses and advanced
practice nurses an overview of cardiovascular
principles and the current state of the science
in genetic testing, disease identification,
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treatment, management, and counseling
about monogenic disorders. Knowledge of
these and other conditions will enable nurses
to engage and contribute as essential mem-
bers of intradisciplinary teams that aim to
improve personalized cardiovascular health.4
The focus will be on long QT syndrome
(LQTS), short QT syndrome (SQTS), Bru-
gada syndrome (BrS), catecholaminergic
polymorphic ventricular tachycardia (CPVT),
and arrhythmogenic right ventricular dyspla-
sia/cardiomyopathy (ARVD/C). An overview
of the genotype, phenotype, and electrocar-
diogram characteristics of each of these con-
ditions is presented, as are the approaches to
treatment and management. A useful glossary
of genetic terms is available on the National
Human Genome Research Institute website
(http://www.genome.gov/glossary.cfm).
Mendelian Genetics
Autosomal Dominant
The method by which certain monogenic
diseases are transmitted depends on chromo-
somal location and nature of the mutation.2
In autosomal dominant transmission, 1 copy
of the mutated gene is sufficient to cause the
expression of the disease and/or the pheno-
type and associated symptoms. If autosomal
dominant patterns of inheritance are present,
a 50% chance exists that the genetic variant
will be passed on to each offspring (Figure 1).
However, the expression, penetrance, and
phenotype of the monogenic condition can
vary greatly, even within members of the
same family who have the same mutation.
Autosomal Recessive
In autosomal recessive patterns of inheri-
tance, 2 copies of the abnormal gene must be
present (ie, both parents must be carriers of
the gene) for the affected gene to be expressed
in the offspring. In autosomal recessive pat-
terns, typically a 25% chance exists that the
offspring will express the given trait and a
50% chance exists that the offspring will be
a carrier, which causes susceptibility for fur-
ther generations to inherit the condition.
Family History and
Genetic Testing
Family history is a powerful tool in risk
assessment.12 Family pedigrees are essential in
delineating modes of transmission and guid-
ing the diagnosis of many of the inherited
VO L U M E 2 9 • N U MB E R 1 • S PRING 2018 CA RD IAC CH A NNE LOPAT H IE S

Unaffected Male (aa)

Unaffected Female (aa)
Affected Male (Aa)
Affected Female (Aa)
Aa aa

Aa aa aa Aa aa Aa

Aa aa Aa aa aa Aa Aa

aa Aa Aa aa

Figure 1: Long QT syndrome autosomal dominant pattern of inheritance. Pedigree demonstrating the autosomal
dominance pattern of inheritance of long QT syndrome. The first-generation affected male, who has 4 children,
has a 50% chance of passing on the condition with each child. In this case, 3 of the 4 children (2 boys and 1
girl) inherited long QT syndrome from their father. In turn, each child of each of these second-generation children
is also at risk of inheriting long QT syndrome from their affected parent, highlighting the importance of cascade
screening in their children.

cardiac channelopathies. Monogenic condi- the clinical presentation, phenotype, and

tions are passed on through autosomal domi-
nant and autosomal recessive Mendelian
modes of transmission.2 Pedigrees are used
to reveal modes of disease transmission in
families, to diagnose disease efficiently in
individuals, and to guide cascade screening
of additional family members who may be
at risk for an inherited condition.
Nurses and other health care profession-
als must be able to recognize red flags within
the family history to facilitate appropriate
referrals and diagnostic evaluation, which
may include genetic testing. Genetic testing
is guided by a comprehensive assessment that
considers not only the family history but
phenotype, environment, symptoms, lifestyle
choices, and other clinical and diagnostic
findings.12 Interdisciplinary collaboration
within the health care team is essential so
the most relevant genetic panel is ordered
for a patient and their family. Genetic testing
is available for many of the cardiac chan-
nelopathies; test selection is informed by
family history. With the widespread avail-
ability of genetic testing, health care profes-
sionals must understand the importance of a
tailored approach to treatment and manage-
ment of the clinical phenotype and the utility
of genetic testing to enhance and improve
clinical care.
Long QT Syndrome
Long QT syndrome is characterized by
delayed repolarization of the cardiac electrical
cycle in the heart, which can lead to serious
ventricular arrhythmias.2 The estimated inci-
dence of LQTS is approximately 1 in 2500
individuals.13 The mortality rate of untreated
LQTS is approximately 50%14-17 and LQTS
can result in syncope, ventricular arrhyth-
mias, and sudden cardiac death in patients
who are known to have otherwise structurally
normal hearts.18 Long QT syndrome usually
is transmitted through an autosomal dominant
mode of inheritance; autosomal recessive
modes of transmission are less common.19,20

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Table 1: Cardiac Channelopathies

Types and Commonly Associated Method of

Genes Inheritance Protein
LQTS
 LQTS1: KCNQ1 AD, AR Potassium channel α subunit
 LQTS2: KCNH2 AD Potassium channel α subunit (hERG)
 LQTS3: SCN5A AD, AR Sodium channel α subunit, type V
 LQTS4: ANK2 AD Ankyrin-2
 LQTS5: KCNE1 AD, AR Potassium channel, member 1
 LQTS6: KCNE2 AD Potassium channel, member 2
 LQTS7: KCNJ2 AD Potassium channel, inwardly rectifying member 2
 LQTS8: CACNA1C AD Calcium channel, L type
 LQTS9: CAV3 AD, AR Caveolin 3
 LQTS10: SCN4B AD Sodium channel β subunit, type IV
 LQTS11: AKAP9 AD A-Kinase anchor protein 9
 LQTS12: SNTA1 AD A-Syntrophin
 LQTS13: KCNJ5 AD Potassium channel, inwardly rectifying, member 5
 LQTS14: CALM1 AD Calmodulin 1
 LQTS15: CALM2 AD Calmodulin 2
SQTS
 SQTS1: KCNH2 AD Potassium channel α subunit (hERG)
 SQTS2: KCNQ1 AD, AR Sodium channel α subunit type X
 SQTS3: KCNJ2 AD Sodium channel β subunit type I
 SQTS4: CACNA1C AD Sodium channel β subunit type II
 SQTS5: CACNB2 AD Sodium channel β subunit type III
CPVT
 CPVT1: RyR2 AD Ryanodine receptor
 CPVT2: CASQ2 AR Calquestrin protein 2
ARVD/C
 PKP2 AD Plakophilin 2
 DSG2 AD Desmoglein
 DSP AD, AR Desmoplakin
 DSC2 AD, AR Desmocollin

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ARVD/C, arrhythmogenic right ventricular dysplasia/cardiomyopathy; CPVT,
catecholaminergic polymorphic ventricular tachycardia; LQTS, long QT syndrome; SQTS, short QT syndrome.

Extensive research has revealed more than
a dozen gene alterations related to LQTS
(Table 1).21-28 Clinical gene sequencing is avail-
able to assess which specific gene may be
responsible for the LQTS in a specific patient.
This crucial information informs the practitio-
ner about the risk, related factors, and associ-
ated physical activities that may trigger an
arrhythmic event.29,30 The 3 most commonly
affected genes in LQTS, KCNQ1 (LQTS
type 1 [LQTS1]), KCNQ2/HERG (LQTS
type 2 [LQTS2]), and SCN5A (LQTS type
3 [LQTS3]), are responsible for most LQTS
cases; however, numerous other types of
LQTS exist (Table 1).
Long QT syndrome type 1 is caused by a
mutation in the KCNQ1 gene.31 Typically,
patients with LQTS1 experience arrhythmic
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episodes in response to exercise or physical
exertion, particularly swimming.2 Adolescent
boys tend to experience more cardiac events
than adolescent girls, whereas, in adults,
women experience more events than men.29,32
This phenomenon is thought to be due to
the cardiac protective effects of testosterone
in boys once they reach puberty, which may
shorten the QT interval.33 In contrast, estro-
gen may affect the potassium channel func-
tion, leading to a prolonged QT interval and
an increased risk for arrhythmia during adult-
hood.33-36 Furthermore, female patients tend
to have a longer baseline QTc than do male
patients, predisposing female patients to
drug-induced LQTS arrhythmic episodes. In
addition, menses and pregnancy may alter
female hormonal levels significantly and
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Table 2: Distinctive Characteristics of Long QT Syndrome Types on Electrocardiogram
LQTS Type Genotype Electrocardiograph Tracing48
1 KCNQ1
2 KCNH2/HERG
3 SCN5A
Abbreviation: LTQS, long QT syndrome.
influence ion channel functionality within
the cardiac myocytes.37,38
Long QT syndrome type 2 is caused by
mutations in the KCNQ2/HERG gene.2
Arrhythmic events can be caused by emo-
tional or auditory triggers (eg, a ringing
alarm clock).2,39 Sex does not play a role in
the number of events experienced by patients
with LQTS22; however, adolescent girls and
postpartum women are at a higher risk of
experiencing cardiac arrhythmic events due
to changes in sex hormone production.40-42
Long QT syndrome type 3 is caused by
mutations in the sodium channel; the SCNA5
gene is the most commonly affected. Long QT
syndrome type 3 accounts for an estimated 5%
to 10% of LQTS cases.43,44 Cardiac events in
patients with LQTS3 commonly occur during
sleep, rest, or periods of bradycardia.2
Greater than 92% of LQTS cases are caused
by loss-of-function mutations in the KCNQ1,
KCNH2, and SCN5A genes that result in
LQTS1, LQTS2, and LQTS3, respectively.
However, approximately 15% to 20% of
LQTS cases do not have a clear genetic link.45
Electrocardiogram Characteristics
The electrocardiogram (ECG) is an effec-
tive tool for diagnosing LQTS in patients
(Table 2).46 The distinctive characteristic of
LQTS on the ECG is extended prolongation
of the QT interval along with the possible
presence of T waves that vary in amplitude
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T-Wave Morphology Triggers
Broad based, peaked Exercise and
physical strain
(eg, swimming)
Low amplitude, Auditory and
flattened emotional (eg,
loud sounds)
Extended ST Sleep and periods
segment with a of rest
narrow, late onset
and shape.47,48 Patients with LQTS1 typically
have tall, peaked T waves on ECGs, whereas
patients with LQTS2 exhibit T waves that
are notched, and patients with LQTS3 tend
to have a longer isoelectric line after the QRS
followed by the T wave.46,48 However, many
patients with LQTS may not have an abnor-
mal ECG; in fact, approximately one-third of
patients with LQTS have a normal ECG and
are at risk for future arrhythmic episodes.29,49
Although most individuals with LQTS do
exhibit clear QT interval prolongation, approx-
imately 10% to 40% do not exhibit QT pro-
longation at rest.29,43,50,51 If a patient’s ECG
tracing does not show QT prolongation,
exercise testing and catecholamine-induced
stress testing may unmask a prolonged QT
and the presence of ventricular ectopy.52-55
Genetic Testing, Family Screening
Genetic testing can confirm an LQTS diag-
nosis and is recommended for those who have
a clinical presentation, ECG morphology, fam-
ily history, and arrhythmias during exercise
and/or stress testing that suggest underlying
LQTS.56 Generally, genetic testing for LQTS
is recommended for all patients who exhibit
a phenotype of QT prolongation on the ECG,
even if other symptoms are not present.45 The
yield of genetic testing is approximately 75%
for the 3 main LQTS subtypes.39 Genetic testing
is recommended for first-degree relatives of the
patient once an LQTS-associated mutation has
H I C K EY AN D E LZ O MOR
been identified.57,58 By recognizing the LQTS
genotype, the clinician can provide better rec-
ommendations about therapies, such as spe-
cific types of β-blockers or antiarrhythmics.39
A thorough analysis of the family history
and genetic testing is required to rule out
LQTS conclusively, even if the clinical presen-
tation and ECG are negative for the charac-
teristics of LQTS. A lack of QT prolongation
on an ECG may be present in up to 25% of
individuals who possess an LQTS-associated
mutation.29,49 Genetic testing for mutations in
the KCNQ1, KCNH2, and SCN5A genes can
confirm the diagnosis of LQTS1, LQTS2, and
LQTS3, respectively, in approximately 75% of
patients, and may guide clinical management.45
Treatment for Long QT Syndrome
β-blockers are used to treat most patients
with LQTS59-62 and are recommended to reduce
ventricular arrhythmias. However, patients
with LQTS2 may not be as responsive to
β-blocker therapy as those with LQTS1.63
Nadolol has proven to be the only β-blocker
successful in preventing arrhythmic episodes
effectively in patients with LQTS2.64 Because
of its effectiveness in targeting the late sodium
current that causes arrhythmias, propranolol
is recommended for patients who have been
diagnosed with LQTS3. Flecainide, ranola-
zine, and mexiletine may be incorporated
with propranolol to create a more effective
treatment plan for patients with LQTS3.65-67
Cardioverter defibrillator (ICD) implanta-
tion is recommended for patients who are
diagnosed as having LQTS and who have
had a cardiac arrest, as well as for patients
who, even when receiving β-blockers, have
experienced repeated syncopal episodes or
ventricular arrhythmias.14,68 Additionally,
patients with 2 or more gene mutations that
can cause LQTS should be considered for
prophylactic ICD implantation.20 Nurses
and other members of the interdisciplinary
team should discuss with the patient and
family what to expect with placement of an
ICD, along with the need for routine follow-up.
Additionally, patients should be educated
about what to do if they experience an ICD
shock, including how to communicate with
the team if an event such as syncope occurs.61,62
Routine counseling for those with LQTS
should include teaching patients how to avoid
dehydration and low potassium states (eg,
during a viral syndrome) that could trigger
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an arrhythmia. In addition, patients and their
families should be aware that some commonly
prescribed drugs, such as antibiotics, may
be associated with prolonging the QT inter-
val and could increase the risk of serious
arrhythmic episodes in patients with LQTS.
A comprehensive list of drugs to be avoided
by patients with LQTS can be found at the
Sudden Arrhythmia Death Syndromes web-
site (www.sads.org) and should be provided
to patients and families as part of their genetic
counseling.69 Patients should be encouraged
to disclose their LQTS condition with their
personal clinicians to help guide clinical care.
Short QT Syndrome
Short QT syndrome, first described in
2000,70 is a channelopathy associated with
atrial fibrillation that can lead to ventricular
arrhythmias (eg, ventricular tachycardia,
ventricular fibrillation) and sudden cardiac
death.70 Although SQTS is not very common,
the effects of arrhythmias are serious and
could be life threatening. Opinions differ
about the official diagnosis of SQTS, espe-
cially concerning the cutoff value for the
lower-limit QT/QTc interval on the ECG;
typically, a QT interval shorter than 330
milliseconds has been used as a guide.71-74
Short QT syndrome is known for its variable
severity and penetrance in patients, ranging
from asymptomatic to sudden cardiac death.
Electrocardiogram Characteristics
Short QT syndrome manifests on the
ECG with an abnormal short QT interval
and peaked T wave (Figure 2).45 An exact QT
interval cutoff for the diagnosis of SQTS has
yet to be determined.73,74 However, in 1 study,
patients with a short QT interval (< 340 ms)
were younger (mean [standard deviation (SD)]
age = 39.2 [8] years) compared with those
with a normal QT interval (360-450 ms), who
were slightly older (mean [SD] age = 44 [8.4]
years) and had a lower heart rate and blood
pressure but were not at an increased risk of
sudden death.75
Genetic Testing, Family Screening
The genes KCNH2, KCNQ1, and KCNJ2
are associated with SQTS types 1, 2, and 3,
respectively.45 Nurses and other members of
the interdisciplinary team may suspect SQTS
based on clinical presentation, family his-
tory, and the ECG. Genetic testing can be
VO L U M E 2 9 • N U MB E R 1 • S PRING 2018 CA RD IAC CH A NNE LOPAT H IE S
I V1
II
III
aVR
aVL
aVF
Figure 2: A 12-lead electrocardiogram of an individual with short QT syndrome. Arrows are pointing to short
QT intervals of approximately 220 milliseconds.
considered. If an individual is known to have
a genetic mutation associated with SQTS,
immediate family members and relatives
should undergo cascade genetic screening for
that specific genetic variant.45
Treatment for Short QT Syndrome
Individuals with SQTS may be treated
with an ICD to decrease the risk of sudden
cardiac death due to ventricular arrhyth-
mias.76 In some individuals, quinidine may be
prescribed to prolong the QT interval; how-
ever, the efficacy of this drug is still under
clinical evaluation.77-79
Brugada Syndrome
In the United States and Europe, the inci-
dence of BrS is estimated to be between
0.01% and 0.03%.80,81 Countries in Southern
Asia, however, have higher incidence of BrS
among the general population.82 Brugada syn-
drome is a channelopathy that usually results
from decreases in the influx of sodium within
the cardiac myocytes.71 In the Brugada geno-
type, either a decrease in the inward sodium
or calcium currents or a decrease in the out-
ward potassium currents within the cell have
been linked to BrS.45,71 More than 8 known
genes are linked to BrS; of these, SCNA5 is
the most commonly affected.45 SCNA5 is the
same gene involved in LQTS3 and the
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V2
V3
V4
V5
V6
clinical phenotype and the ECG for each
may have similarities.
Individuals with BrS may exhibit serious,
life-threatening arrhythmias or be asymptom-
atic. For BrS to be diagnosed clinically, individ-
uals must exhibit at least one of the following:
(1) type-1 Brugada ECG pattern, (2) syncopal
episodes, and (3) a family history of sudden
death.82 Thus, obtaining a thorough family
history and a complete medical history and
an ECG are important.
Brugada syndrome exhibits 3 distinct ECG
patterns, known as type 1, type 2, and type 3.
The type 1 ECG pattern is known diagnosti-
cally for its clinical surreptitiousness. Type 1
is expected to have a much higher incidence
of ventricular events.83 An otherwise normal
ECG may change to a Brugada ECG pattern
in the presence of a fever, although the exact
pathophysiology is not understood.71,84 Thus,
a health care clinician must try to obtain an
ECG in the setting of a fever if BrS is suspected.
Practitioners must understand that medications
must be administered quickly to reduce a
fever and to avoid ventricular arrhythmias in
patients who have a known history of BrS.
Electrocardiogram Characteristics
The hallmark of BrS on the ECG is ST
elevation in the right precordial leads V1 to
V2-V3 (Figure 3).84 Three types of ST-elevation
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I aVR
II aVL
III aVF
V1
Figure 3: Electrocardiogram characteristics of patients with Brugada syndrome. Arrows indicate the typical
Brugada type 1 pattern.
ECG patterns are associated with BrS: type
1, type 2, and type 3.71 Typically, diagnosis of
BrS involves discerning the classical type 1
ECG pattern, coupled with a family history
of syncope and sudden death.82,85 Type 2 and
type 3 ECG patterns do not confirm a diag-
nosis of BrS and/or do not necessitate genetic
testing or family screening.45 Both precordial
leads (ie, V1 and V2) can be placed in a more
superior position than the standard 12-lead
ECG placement; this involves moving V1 and
V2 up to the third intercostal space from their
traditional placement in the fourth intercostal
space to discern the BrS ECG pattern.86,87
Type 1 BrS is diagnosed when the ECG pat-
tern is triggered spontaneously or in response
to medications that further inhibit sodium-
channel functions, such as certain antiar-
rhythmics, psychotropics, and analgesics.69
Genetic Testing, Family Screening
Genetic testing can play an important role
in properly diagnosing or guiding care in an
ambiguous clinical presentation. Although
genetic testing is helpful in confirming a
diagnosis of BrS, a complete family history
may help identify other at-risk individuals
within a family regardless of the phenotype.
The SCN5A gene, which controls the sodium
channel within the cardiac cells, is responsi-
ble for more than 75% of BrS cases, yet
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V1
V2
V3
genetic testing of SCN5A has an estimated
yield of 20% to 30%.88 Most BrS cases are
genetically ambiguous and the exact gene
involvement is unknown.45 Cascade screening
is recommended in the current guidelines for
family members for whom a specific mutation
has been identified to help with risk stratifi-
cation and guide clinical care.45
Treatment for Brugada Syndrome
Patients who experience serious arrhythmic
events due to BrS may have an ICD implanted
to treat subsequent ventricular arrhythmias.71
Patients who experience a cardiac arrest are
recommended for ICD implantation, regard-
less of any other clinical variables.82 However,
current guidelines do not recommend implan-
tation of an ICD in asymptomatic patients
with BrS, because they are believed to be at
low risk for ventricular arrhythmias.30 Quini-
dine and isoproterenol89 increase cellular lev-
els of sodium and calcium while inhibiting
potassium levels and may be prescribed to
balance the sodium ionic currents within the
cardiac myocytes.71 Findings of one study
indicated use of quinidine may reduce the
risk of ventricular arrhythmias, particularly
ventricular fibrillation, that could lead to
arrhythmic death in certain subgroups of
patients.90 Quinidine use is warranted when
ICD implantation is contraindicated or when
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patients experience multiple shocks from their
ICD or exhibit supraventricular arrhythmias.91
Practitioners must advise those with a diagno-
sis of BrS to avoid drugs known to slow the
function of the sodium channels and poten-
tially induce ventricular arrhythmias.92 All
members of the health care team should talk
about drugs to avoid as part of patient coun-
seling. Brugadadrugs.org provides a list of
drugs to be avoided.93
Catecholaminergic Polymorphic
Ventricular Tachycardia
Catecholaminergic polymorphic ventricu-
lar tachycardia is a channelopathy that can
disrupt normal calcium-channel ionic flow
within the cardiac myocytes of the heart.94
CPVT typically is diagnosed in younger adults
(< 40 years old), with a primary onset between
age 7 to 12 years in patients who have a struc-
turally normal heart.71,95
Approximately 1 in 10 000 individuals is
affected by CPVT,71 which is characterized
by catecholamine-induced episodic syncope,
ventricular tachycardia, and sudden cardiac
death, typically occurring during physical
exercise or emotional stress95-97 when arrhyth-
mias usually are triggered by release of cate-
cholamines (ie, epinephrine, norepinephrine,
and dopamine). CPVT has an extraordinarily
high incidence of lethal ventricular arrhythmias
and sudden cardiac death, with a mortality rate
of up to 30% in undiagnosed and untreated
patients younger than 40 years.98,99 Up to one-
third of patients with CPVT have experienced
at least 1 cardiac arrest in their lifetime.95
Electrocardiogram Characteristics
Patients with CPVT typically have a nor-
mal resting ECG; however, physical exertion
or emotional stress can alter their baseline
ECG. These changes may include premature
ventricular complexes, nonsustained ventric-
ular tachycardia, and ventricular fibrillation.
The ECG can be used in combination with
family history, clinical presentation, and genetic
testing to help confirm a diagnosis of CPVT.71
The ECG of an individual with CPVT typi-
cally shows a normal sinus rhythm at rest
with no abnormalities. However, during an
exercise stress test97 or in the setting of an
emotional event, an individual with CPVT
may exhibit bidirectional ventricular tachy-
cardia and polymorphic ventricular tachycar-
dia. Bidirectional ventricular tachycardia is
51
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categorized by 2 abnormal QRS waves that
regularly alternate (Figure 4). Ventricular
tachycardia can result in syncope, ventricular
arrhythmias, cardiac arrest, and sudden car-
diac death, making this a rare but potentially
life-threatening inherited channelopathy.94
Genetic Testing, Family Screening
Genetic testing of individuals suspected
of having CPVT is highly recommended.45
The autosomal dominant form of transmis-
sion of CPVT involves alteration in the RyR2
gene. The autosomal recessive form of CPVT
involves variation in the CASQ2 gene.100 The
dominant RyR2 form of CPVT occurs in
approximately 65% of patients with CPVT,
whereas the CASQ2 variant form affects
approximately 3% to 5% of individuals.45,71
Genetic testing of patients in whom CPVT was
diagnosed clinically has a positive mutation
yield rate of approximately 65%.98,101 Other
genes also have been suspected to be involved
in a similar expression of CPVT; however,
details of their involvement are evolving.102,103
Genetic testing is required to confirm the
diagnosis of CPVT.101 Once a pathogenic
variation related to CPVT is identified, first-
degree and second-degree relatives of the
proband should be assessed genetically and
clinically by cardiac stress testing to see if
the release of catecholamines results in induced
ventricular arrhythmias.45 Stress testing is used
because physical exercise promotes the release
of catecholamines that may result in premature
ventricular complexes that develop, in turn,
into bidirectional or polymorphic ventricular
tachycardia.45 In instances when patients are
unable to undergo regular stress testing because
of orthopedic issues or other conditions that
restrict mobility, a catecholamine-induced
drug challenge using epinephrine or isopro-
terenol can simulate exercise.71 The practitioner
should understand that screening is a funda-
mental part of the identification of at-risk
individuals who may have CPVT.
Treatment for CPVT
After receiving a diagnosis and counseling,
patients should be prescribed an appropriate
β-blocker to lower the risks of future arrhyth-
mic episodes significantly. Nadalol is viewed
as the most effective β-blocker for treating
patients with CPVT.94 Propranolol also is effec-
tive, although β-blockers do not fully protect
individuals with CPVT from experiencing
H I C K EY AN D E LZ O MOR
I V1
II V2
III V3
aVR V4
aVL V5
V6
aVF
* * * * * * * * * * * * *
Figure 4: Electrocardiogram of patient with CPVT during exercise. Asterisks mark polymorphic ventricular
beats. Image courtesy of Dr C van der Werf and ECGpedia.org.
Abbreviation: CPVT, catecholaminergic polymorphic ventricular tachycardia.
arrhythmic events.99 Genetic testing is espe-
cially important for younger children in fami-
lies in which a causative CPVT pathogenic
mutation has been identified; medication can
be initiated and counseling provided about
avoiding stressful situations.45
Arrhythmogenic Right
Ventricular Dysplasia/
Cardiomyopathy
Arrhythmogenic right ventricular dyspla-
sia/cardiomyopathy is known for its abnormali-
ties in structure and fatty infiltrates, typically
within the right ventricle,104,105 and is a major
cause of ventricular arrhythmias in patients
aged 35 years or younger.106,107 The structural
abnormalities lead to functional changes and
thinning of the right ventricle, resulting in
abnormal motion, structure, and conduction
within the heart. Wall motion abnormalities,
dilation, ventricular aneurysms, and increased
trabeculation in the right ventricle develop
over time.108 ARVD/C results in inflammation
and loss of myocytes, which affect proper
electrical conduction.45
Many genes have been linked to ARVD/C
onset. The 4 main genes associated with
52
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W W W.A ACNACCONLINE .ORG
* * * * * * * * * *
ARVD/C are PKP2, DSG2, DSP, and DSC2.
All 4 genes code for desmosomal proteins,
which are responsible for cell linkage and
proper adhesion and structure within the
heart.109-117 One study found that approxi-
mately 70% of families with ARVD/C had
mutations in the PKP2 gene.118 Nurses must
understand that ARVD/C can be difficult to
diagnose based on genetic testing alone;
research has found that variations in the
PKP2 and DSG2 genes may not necessarily
cause the phenotypical expression of
ARVD/C.119,120
ARVD/C may have no initial symptoms
or no observed ECG or echocardiogram
abnormalities until the disease progresses.
Hallmark findings include right ventricular
dilation with thinning of the right ventricu-
lar wall over time, which can result in aneu-
rysms, cardiac wall abnormalities, entire
loss of ventricular function, ventricular
arrhythmias, and sudden cardiac death.108
ARVD/C is a rare, genetically inherited
channelopathy that can result in changes to
the heart’s electrical conduction system, as
well as a cardiomyopathy resulting in struc-
tural changes and dilation.121
VO L U M E 2 9 • N U MB E R 1 • S PRING 2018 CA RD IAC CH A NNE LOPAT H IE S
Electrocardiogram Characteristics
A hallmark finding on the ECG that
would lead a practitioner to suspect ARVD/C
is the epsilon wave (Figure 5). An epsilon
wave only occurs in an estimated one-third
of individuals.122 In addition, a right bundle
branch block, ventricular tachycardia, and
T-wave inversions in leads V1-V3 may be
seen on the ECG. These ECG findings are
due to the fibro-fatty infiltration in the right
ventricle, which is the most common histo-
logic finding. The most common arrhythmia
is ventricular tachycardia, which originates
in the right ventricle and therefore has a left
bundle branch block pattern.45
Genetic Testing, Family Screening
Typically, ARVD/C is transmitted in an auto-
somal dominant fashion. However, environ-
mental and genetic factors as well as age may
contribute to variable penetrance among indi-
viduals, even those in the same family.123-125
Other forms of Mendelian inheritance, such
as autosomal recessive, compound heterozy-
gosity, and digenic heterozygosity occur with
ARVD/C.109,110,119,126-128 Compound heterozygos-
ity refers to individuals who possess 2 differ-
ent disease alleles of a single gene that can
cause ARVD/C.129 Digenic heterozygosity refers
to a phenomenon by which a person coinher-
its disease alleles for 2 genes.
Approximately 33% of ARVD/C genetic
variations are false positives.130 Thus, the inter-
disciplinary team should exhibit vigilance
when ordering genetic testing and interpreting
the subsequent results. Given the relatively
new and developing use of genetic testing for
ARVD/C diagnosis, practitioners are advised
to take the entire patient profile, family
Table 3: Diagnostic Criteria for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
Major Diagnostic Criteria
Magnetic resonance imaging shows thinning of
right ventricle free wall
Endomyocardial biopsy with fibro/fatty infiltrates
Epsilon wave on electrocardiogram
QRS interval prolongation > 110 ms
Right ventricle exhibits segmental dilation
Localized right ventricle aneurysms
Severe dilation of the right ventricle
Decreased ejection fraction of the right ventricle
Autopsy or surgery confirmation of ARVD/C
Abbreviation: ARVD/C, arrhythmogenic right ventricular dysplasia/cardiomyopathy. Adapted from Andrews et al.132
53
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V1
Figure 5: Electrocardiogram showing the hallmark
finding of an epsilon wave (arrow) that may lead a
practitioner to suspect arrhythmogenic right ventricu-
lar dysplasia/cardiomyopathy. Image courtesy of Dr
De Voogt and ECGpedia.org.
history, and presentation into account, along
with confirmatory testing, before diagnosing
ARVD/C. In this way, genotyping is support-
ive of the clinical presentation of ARVD/C
in the proband.131
Overall, genetic testing is recommended for
patients when they exhibit 1 or 2 diagnostic
criteria (Table 3).132 If a patient has a muta-
tion linked to ARVD/C, subsequent genetic
testing of family members and relatives is rec-
ommended.45 However, testing is not recom-
mended for patients who only have 1 minor
diagnostic criterion linked to ARVD/C.45
Individuals and families are encouraged
to be evaluated at a center that has cared for
those with ARVD/C and is experienced in
genetic testing and counseling families with
complex genetic conditions. In addition, imme-
diate family members of a proband may opt
to be tested and monitored for the develop-
ment of ARVD/C.131 Given ARVD/C’s complex
Minor Diagnostic Criteria
Family history of sudden cardiac death in individuals
< 35 years old
Known family history of ARVD/C
Many premature ventricular complexes
Ventricular tachycardia with left bundle branch block
Inverted T-wave morphology in the V1-V3 leads, with
no presence of right bundle branch block
Right ventricular hypokinesis and dilation
Moderate right ventricular dilation, with or without
decreased right ventricular ejection fraction, with
normal left ventricular functioning
H I C K EY AN D E LZ O MOR
genetic background and varying penetrance,
nurses must understand that a negative genetic
test for ARVD/C-causative mutations does
not negate the development of the condition
in the future.108,119
Treatment for ARVD/C
The primary goals for treating ARVD/C
are to reduce the frequency and severity of
arrhythmias and to prevent or limit worsen-
ing of heart failure (per standard guidelines45)
and ventricular function. The optimal strate-
gies for prevention of sudden cardiac death
in patients with ARVD/C include ICD therapy,
medications, and catheter ablation. Medica-
tions such as β-blockers and antiarrhythmics
can be used to decrease the number and sever-
ity of arrhythmias. If medications fail to pre-
vent ventricular tachycardia, catheter ablation
may be considered. Although catheter abla-
tion is not a cure for ARVD/C, it may reduce
the number of ventricular arrhythmias treated
by ICD therapy.121
Conclusion
Nurses must stay abreast of new and evolv-
ing knowledge in genetics. Understanding the
pathophysiology, recognizing the characteris-
tic ECG findings, and understanding the role
of diagnostic testing and prescribed therapies
such as β-blockers and ICDs will improve
personalized clinical care approaches. Nurses
play a critical role in providing clinical care,
counseling, and education to patients and
families who have inherited channelopathies.
ACKNOWLEDGMENTS
We thank Teresa C. Riga for assisting with
the preparation of this manuscript.
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 Cardiac Channelopathies: Recognition, Treatment, Management
Kathleen T. Hickey and Amir Elzomor
AACN Adv Crit Care 2018;29 43-57 10.4037/aacnacc2018664
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