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AACN Advanced Critical Care

Volume 29, Number 1, pp. 43-57

© 2018 AACN

Cardiac Channelopathies:
Recognition, Treatment, Management
Kathleen T. Hickey, FNP-BC, ANP-BC, EdD
Amir Elzomor

The discovery of the human genome has cardiac channelopathies, electrocardiogram
ushered in a new era of molecular testing, characteristics, approaches to treatment, and
advancing our knowledge and ability to iden- care for patients and their families. This article
tify cardiac channelopathies. Genetic varia- provides an overview of cardiac channelopa-
tions can affect the opening and closing of the thies that nurses might encounter in an array
potassium, sodium, and calcium channels, of clinical and research settings, focusing on
resulting in arrhythmias and sudden death. the clinically relevant features of long QT
Cardiac arrhythmias caused by disorders of syndrome, short QT syndrome, Brugada
ion channels are known as cardiac channelo- syndrome, catecholaminergic polymorphic
pathies. Nurses are important members of ventricular tachycardia, and arrhythmogenic
many interdisciplinary teams and must have right ventricular dysplasia/cardiomyopathy.
a general understanding of the pathophysiol- Keywords: genetics, cardiac, channelopathy,
ogy of the most commonly encountered arrhythmia, sudden cardiac death

W ith advancements in molecular genet-

ics, our knowledge of common and
rare cardiac conditions has improved and a
affect the opening and closing of the potas-
sium, sodium, and calcium channels, resulting
in ionic changes across the cardiac membrane
new era of precision medicine has been ush- that may lead to arrhythmias and sudden
ered in.1 However, despite the growth of our death.2 An understanding of the molecular
knowledge of cardiovascular genomics con- pathophysiology, electrocardiogram charac-
cepts, the application of genetic information teristics, and clinical presentation can guide
to improve personalized clinical outcomes nurses and other members of the interdisci-
remains to be implemented fully in clinical plinary team in implementing an effective
practice.2 With almost 3 million nurses work- plan of care.
ing in the United States,3 nursing is indispens- Polygenic conditions such as diabetes, obe-
able in the roles of integrating health care sity, heart disease, dyslipidemia, and stroke
advancements, enhancing genomic literacy,
and increasing proficiency in recognizing
inherited cardiovascular conditions. Genomic Kathleen T. Hickey is Professor of Nursing, Columbia University
knowledge is fundamental to ensuring clinicians Medical Center, 622 W 168th St, New York, NY 10032
recognize common and rare cardiac condi- (

tions and have the necessary competencies to Amir Elzomor is a premedical student at the Albert Dorman
understand and manage these conditions.4 Honors College at the New Jersey Institute of Technology,
Cardiac arrhythmias caused by disorders Newark, New Jersey.

of ion channels are known as cardiac chan- The authors declare no conflicts of interest.
nelopathies. These genetic variations can DOI:

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have complex traits (ie, multiple genes and treatment, management, and counseling
interactions that are influenced by behavioral about monogenic disorders. Knowledge of
and environmental factors).2 Coronary artery these and other conditions will enable nurses
disease, the leading cause of death in the United to engage and contribute as essential mem-
States,5 comprises a broad spectrum of clini- bers of intradisciplinary teams that aim to
cal entities, including myocardial infarction improve personalized cardiovascular health.4
and sudden cardiac death, and is associated The focus will be on long QT syndrome
with a complex heterogeneity of gene and (LQTS), short QT syndrome (SQTS), Bru-
environmental interactions.6 Although studies gada syndrome (BrS), catecholaminergic
have established genetic markers for prema- polymorphic ventricular tachycardia (CPVT),
ture coronary artery disease, hyperlipidemia, and arrhythmogenic right ventricular dyspla-
and other polygenic conditions,7,8 the specific sia/cardiomyopathy (ARVD/C). An overview
degree of influence of an individual’s genetic of the genotype, phenotype, and electrocar-
predisposition versus his or her lifestyle and diogram characteristics of each of these con-
environment has been more difficult to estab- ditions is presented, as are the approaches to
lish.2 Inherited defects in the low-density lipo- treatment and management. A useful glossary
protein receptor can result in a genetic variation of genetic terms is available on the National
in the apolipoprotein B gene, which can impair Human Genome Research Institute website
the ability of cells to remove cholesterol- (
carrying particles from the bloodstream, result-
ing in significant accumulation of cholesterol Mendelian Genetics
in heart tissue, which can lead to premature Autosomal Dominant
coronary artery disease.2,9,10 Along with the The method by which certain monogenic
genetic involvement, an individual’s environ- diseases are transmitted depends on chromo-
ment, such as consuming a high-fat diet with somal location and nature of the mutation.2
the absence of exercise, could be a contribut- In autosomal dominant transmission, 1 copy
ing factor to premature coronary artery dis- of the mutated gene is sufficient to cause the
ease, which could influence the expression expression of the disease and/or the pheno-
of the phenotype.11 type and associated symptoms. If autosomal
Knowledge of gene and environmental dominant patterns of inheritance are present,
influences is evolving and genetic testing and a 50% chance exists that the genetic variant
screening for polygenic cardiovascular disor- will be passed on to each offspring (Figure 1).
ders currently are not available in clinical prac- However, the expression, penetrance, and
tice. However, understanding of the numerous phenotype of the monogenic condition can
monogenic disorders has grown, allowing for vary greatly, even within members of the
a personalized precision approach to cardio- same family who have the same mutation.
vascular health.4 In particular, major advance-
ments have developed in understanding the Autosomal Recessive
underpinnings of the monogenetic or single- In autosomal recessive patterns of inheri-
gene disorders (inherited channelopathies) tance, 2 copies of the abnormal gene must be
of the heart. present (ie, both parents must be carriers of
The heart beating is the result of a delicate the gene) for the affected gene to be expressed
balance of sodium ions, potassium ions, and in the offspring. In autosomal recessive pat-
calcium ions at the cellular level. Cardiac chan- terns, typically a 25% chance exists that the
nelopathies can result from underlying genetic offspring will express the given trait and a
abnormalities that cause the ion channels to 50% chance exists that the offspring will be
be dysfunctional, allowing too much or too a carrier, which causes susceptibility for fur-
little sodium, potassium, or calcium to flow ther generations to inherit the condition.
across the cardiac membrane. Tragically, the
initial presentation of an underlying inherited Family History and
arrhythmia can be sudden cardiac death. Genetic Testing
This article provides nurses and advanced Family history is a powerful tool in risk
practice nurses an overview of cardiovascular assessment.12 Family pedigrees are essential in
principles and the current state of the science delineating modes of transmission and guid-
in genetic testing, disease identification, ing the diagnosis of many of the inherited

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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- family history. With the widespread avail-
nant and autosomal recessive Mendelian ability of genetic testing, health care profes-
modes of transmission.2 Pedigrees are used sionals must understand the importance of a
to reveal modes of disease transmission in tailored approach to treatment and manage-
families, to diagnose disease efficiently in ment of the clinical phenotype and the utility
individuals, and to guide cascade screening of genetic testing to enhance and improve
of additional family members who may be clinical care.
at risk for an inherited condition.
Nurses and other health care profession- Long QT Syndrome
als must be able to recognize red flags within Long QT syndrome is characterized by
the family history to facilitate appropriate delayed repolarization of the cardiac electrical
referrals and diagnostic evaluation, which cycle in the heart, which can lead to serious
may include genetic testing. Genetic testing ventricular arrhythmias.2 The estimated inci-
is guided by a comprehensive assessment that dence of LQTS is approximately 1 in 2500
considers not only the family history but individuals.13 The mortality rate of untreated
phenotype, environment, symptoms, lifestyle LQTS is approximately 50%14-17 and LQTS
choices, and other clinical and diagnostic can result in syncope, ventricular arrhyth-
findings.12 Interdisciplinary collaboration mias, and sudden cardiac death in patients
within the health care team is essential so who are known to have otherwise structurally
the most relevant genetic panel is ordered normal hearts.18 Long QT syndrome usually
for a patient and their family. Genetic testing is transmitted through an autosomal dominant
is available for many of the cardiac chan- mode of inheritance; autosomal recessive
nelopathies; test selection is informed by 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
 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
 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
 CPVT1: RyR2 AD Ryanodine receptor
 CPVT2: CASQ2 AR Calquestrin protein 2
 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 episodes in response to exercise or physical
a dozen gene alterations related to LQTS exertion, particularly swimming.2 Adolescent
(Table 1).21-28 Clinical gene sequencing is avail- boys tend to experience more cardiac events
able to assess which specific gene may be than adolescent girls, whereas, in adults,
responsible for the LQTS in a specific patient. women experience more events than men.29,32
This crucial information informs the practitio- This phenomenon is thought to be due to
ner about the risk, related factors, and associ- the cardiac protective effects of testosterone
ated physical activities that may trigger an in boys once they reach puberty, which may
arrhythmic event.29,30 The 3 most commonly shorten the QT interval.33 In contrast, estro-
affected genes in LQTS, KCNQ1 (LQTS gen may affect the potassium channel func-
type 1 [LQTS1]), KCNQ2/HERG (LQTS tion, leading to a prolonged QT interval and
type 2 [LQTS2]), and SCN5A (LQTS type an increased risk for arrhythmia during adult-
3 [LQTS3]), are responsible for most LQTS hood.33-36 Furthermore, female patients tend
cases; however, numerous other types of to have a longer baseline QTc than do male
LQTS exist (Table 1). patients, predisposing female patients to
Long QT syndrome type 1 is caused by a drug-induced LQTS arrhythmic episodes. In
mutation in the KCNQ1 gene.31 Typically, addition, menses and pregnancy may alter
patients with LQTS1 experience arrhythmic 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 T-Wave Morphology Triggers

1 KCNQ1 Broad based, peaked Exercise and

physical strain
(eg, swimming)

2 KCNH2/HERG Low amplitude, Auditory and

flattened emotional (eg,
loud sounds)

3 SCN5A Extended ST Sleep and periods

segment with a of rest
narrow, late onset

Abbreviation: LTQS, long QT syndrome.

influence ion channel functionality within and shape.47,48 Patients with LQTS1 typically
the cardiac myocytes.37,38 have tall, peaked T waves on ECGs, whereas
Long QT syndrome type 2 is caused by patients with LQTS2 exhibit T waves that
mutations in the KCNQ2/HERG gene.2 are notched, and patients with LQTS3 tend
Arrhythmic events can be caused by emo- to have a longer isoelectric line after the QRS
tional or auditory triggers (eg, a ringing followed by the T wave.46,48 However, many
alarm clock).2,39 Sex does not play a role in patients with LQTS may not have an abnor-
the number of events experienced by patients mal ECG; in fact, approximately one-third of
with LQTS22; however, adolescent girls and patients with LQTS have a normal ECG and
postpartum women are at a higher risk of are at risk for future arrhythmic episodes.29,49
experiencing cardiac arrhythmic events due Although most individuals with LQTS do
to changes in sex hormone production.40-42 exhibit clear QT interval prolongation, approx-
Long QT syndrome type 3 is caused by imately 10% to 40% do not exhibit QT pro-
mutations in the sodium channel; the SCNA5 longation at rest.29,43,50,51 If a patient’s ECG
gene is the most commonly affected. Long QT tracing does not show QT prolongation,
syndrome type 3 accounts for an estimated 5% exercise testing and catecholamine-induced
to 10% of LQTS cases.43,44 Cardiac events in stress testing may unmask a prolonged QT
patients with LQTS3 commonly occur during and the presence of ventricular ectopy.52-55
sleep, rest, or periods of bradycardia.2
Greater than 92% of LQTS cases are caused Genetic Testing, Family Screening
by loss-of-function mutations in the KCNQ1, Genetic testing can confirm an LQTS diag-
KCNH2, and SCN5A genes that result in nosis and is recommended for those who have
LQTS1, LQTS2, and LQTS3, respectively. a clinical presentation, ECG morphology, fam-
However, approximately 15% to 20% of ily history, and arrhythmias during exercise
LQTS cases do not have a clear genetic link.45 and/or stress testing that suggest underlying
LQTS.56 Generally, genetic testing for LQTS
Electrocardiogram Characteristics is recommended for all patients who exhibit
The electrocardiogram (ECG) is an effec- a phenotype of QT prolongation on the ECG,
tive tool for diagnosing LQTS in patients even if other symptoms are not present.45 The
(Table 2).46 The distinctive characteristic of yield of genetic testing is approximately 75%
LQTS on the ECG is extended prolongation for the 3 main LQTS subtypes.39 Genetic testing
of the QT interval along with the possible is recommended for first-degree relatives of the
presence of T waves that vary in amplitude patient once an LQTS-associated mutation has

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been identified.57,58 By recognizing the LQTS an arrhythmia. In addition, patients and their
genotype, the clinician can provide better rec- families should be aware that some commonly
ommendations about therapies, such as spe- prescribed drugs, such as antibiotics, may
cific types of β-blockers or antiarrhythmics.39 be associated with prolonging the QT inter-
A thorough analysis of the family history val and could increase the risk of serious
and genetic testing is required to rule out arrhythmic episodes in patients with LQTS.
LQTS conclusively, even if the clinical presen- A comprehensive list of drugs to be avoided
tation and ECG are negative for the charac- by patients with LQTS can be found at the
teristics of LQTS. A lack of QT prolongation Sudden Arrhythmia Death Syndromes web-
on an ECG may be present in up to 25% of site ( and should be provided
individuals who possess an LQTS-associated to patients and families as part of their genetic
mutation.29,49 Genetic testing for mutations in counseling.69 Patients should be encouraged
the KCNQ1, KCNH2, and SCN5A genes can to disclose their LQTS condition with their
confirm the diagnosis of LQTS1, LQTS2, and personal clinicians to help guide clinical care.
LQTS3, respectively, in approximately 75% of
patients, and may guide clinical management.45 Short QT Syndrome
Short QT syndrome, first described in
Treatment for Long QT Syndrome 2000,70 is a channelopathy associated with
β-blockers are used to treat most patients atrial fibrillation that can lead to ventricular
with LQTS59-62 and are recommended to reduce arrhythmias (eg, ventricular tachycardia,
ventricular arrhythmias. However, patients ventricular fibrillation) and sudden cardiac
with LQTS2 may not be as responsive to death.70 Although SQTS is not very common,
β-blocker therapy as those with LQTS1.63 the effects of arrhythmias are serious and
Nadolol has proven to be the only β-blocker could be life threatening. Opinions differ
successful in preventing arrhythmic episodes about the official diagnosis of SQTS, espe-
effectively in patients with LQTS2.64 Because cially concerning the cutoff value for the
of its effectiveness in targeting the late sodium lower-limit QT/QTc interval on the ECG;
current that causes arrhythmias, propranolol typically, a QT interval shorter than 330
is recommended for patients who have been milliseconds has been used as a guide.71-74
diagnosed with LQTS3. Flecainide, ranola- Short QT syndrome is known for its variable
zine, and mexiletine may be incorporated severity and penetrance in patients, ranging
with propranolol to create a more effective from asymptomatic to sudden cardiac death.
treatment plan for patients with LQTS3.65-67
Cardioverter defibrillator (ICD) implanta- Electrocardiogram Characteristics
tion is recommended for patients who are Short QT syndrome manifests on the
diagnosed as having LQTS and who have ECG with an abnormal short QT interval
had a cardiac arrest, as well as for patients and peaked T wave (Figure 2).45 An exact QT
who, even when receiving β-blockers, have interval cutoff for the diagnosis of SQTS has
experienced repeated syncopal episodes or yet to be determined.73,74 However, in 1 study,
ventricular arrhythmias.14,68 Additionally, patients with a short QT interval (< 340 ms)
patients with 2 or more gene mutations that were younger (mean [standard deviation (SD)]
can cause LQTS should be considered for age = 39.2 [8] years) compared with those
prophylactic ICD implantation.20 Nurses with a normal QT interval (360-450 ms), who
and other members of the interdisciplinary were slightly older (mean [SD] age = 44 [8.4]
team should discuss with the patient and years) and had a lower heart rate and blood
family what to expect with placement of an pressure but were not at an increased risk of
ICD, along with the need for routine follow-up. sudden death.75
Additionally, patients should be educated
about what to do if they experience an ICD Genetic Testing, Family Screening
shock, including how to communicate with The genes KCNH2, KCNQ1, and KCNJ2
the team if an event such as syncope occurs.61,62 are associated with SQTS types 1, 2, and 3,
Routine counseling for those with LQTS respectively.45 Nurses and other members of
should include teaching patients how to avoid the interdisciplinary team may suspect SQTS
dehydration and low potassium states (eg, based on clinical presentation, family his-
during a viral syndrome) that could trigger tory, and the ECG. Genetic testing can be

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I V1



aVR V4

aVL V5

aVF V6

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 clinical phenotype and the ECG for each
a genetic mutation associated with SQTS, may have similarities.
immediate family members and relatives Individuals with BrS may exhibit serious,
should undergo cascade genetic screening for life-threatening arrhythmias or be asymptom-
that specific genetic variant.45 atic. For BrS to be diagnosed clinically, individ-
uals must exhibit at least one of the following:
Treatment for Short QT Syndrome (1) type-1 Brugada ECG pattern, (2) syncopal
Individuals with SQTS may be treated episodes, and (3) a family history of sudden
with an ICD to decrease the risk of sudden death.82 Thus, obtaining a thorough family
cardiac death due to ventricular arrhyth- history and a complete medical history and
mias.76 In some individuals, quinidine may be an ECG are important.
prescribed to prolong the QT interval; how- Brugada syndrome exhibits 3 distinct ECG
ever, the efficacy of this drug is still under patterns, known as type 1, type 2, and type 3.
clinical evaluation.77-79 The type 1 ECG pattern is known diagnosti-
cally for its clinical surreptitiousness. Type 1
Brugada Syndrome is expected to have a much higher incidence
In the United States and Europe, the inci- of ventricular events.83 An otherwise normal
dence of BrS is estimated to be between ECG may change to a Brugada ECG pattern
0.01% and 0.03%.80,81 Countries in Southern in the presence of a fever, although the exact
Asia, however, have higher incidence of BrS pathophysiology is not understood.71,84 Thus,
among the general population.82 Brugada syn- a health care clinician must try to obtain an
drome is a channelopathy that usually results ECG in the setting of a fever if BrS is suspected.
from decreases in the influx of sodium within Practitioners must understand that medications
the cardiac myocytes.71 In the Brugada geno- must be administered quickly to reduce a
type, either a decrease in the inward sodium fever and to avoid ventricular arrhythmias in
or calcium currents or a decrease in the out- patients who have a known history of BrS.
ward potassium currents within the cell have
been linked to BrS.45,71 More than 8 known Electrocardiogram Characteristics
genes are linked to BrS; of these, SCNA5 is The hallmark of BrS on the ECG is ST
the most commonly affected.45 SCNA5 is the elevation in the right precordial leads V1 to
same gene involved in LQTS3 and the V2-V3 (Figure 3).84 Three types of ST-elevation

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I aVR 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 genetic testing of SCN5A has an estimated
1, type 2, and type 3.71 Typically, diagnosis of yield of 20% to 30%.88 Most BrS cases are
BrS involves discerning the classical type 1 genetically ambiguous and the exact gene
ECG pattern, coupled with a family history involvement is unknown.45 Cascade screening
of syncope and sudden death.82,85 Type 2 and is recommended in the current guidelines for
type 3 ECG patterns do not confirm a diag- family members for whom a specific mutation
nosis of BrS and/or do not necessitate genetic has been identified to help with risk stratifi-
testing or family screening.45 Both precordial cation and guide clinical care.45
leads (ie, V1 and V2) can be placed in a more
superior position than the standard 12-lead Treatment for Brugada Syndrome
ECG placement; this involves moving V1 and Patients who experience serious arrhythmic
V2 up to the third intercostal space from their events due to BrS may have an ICD implanted
traditional placement in the fourth intercostal to treat subsequent ventricular arrhythmias.71
space to discern the BrS ECG pattern.86,87 Patients who experience a cardiac arrest are
Type 1 BrS is diagnosed when the ECG pat- recommended for ICD implantation, regard-
tern is triggered spontaneously or in response less of any other clinical variables.82 However,
to medications that further inhibit sodium- current guidelines do not recommend implan-
channel functions, such as certain antiar- tation of an ICD in asymptomatic patients
rhythmics, psychotropics, and analgesics.69 with BrS, because they are believed to be at
low risk for ventricular arrhythmias.30 Quini-
Genetic Testing, Family Screening dine and isoproterenol89 increase cellular lev-
Genetic testing can play an important role els of sodium and calcium while inhibiting
in properly diagnosing or guiding care in an potassium levels and may be prescribed to
ambiguous clinical presentation. Although balance the sodium ionic currents within the
genetic testing is helpful in confirming a cardiac myocytes.71 Findings of one study
diagnosis of BrS, a complete family history indicated use of quinidine may reduce the
may help identify other at-risk individuals risk of ventricular arrhythmias, particularly
within a family regardless of the phenotype. ventricular fibrillation, that could lead to
The SCN5A gene, which controls the sodium arrhythmic death in certain subgroups of
channel within the cardiac cells, is responsi- patients.90 Quinidine use is warranted when
ble for more than 75% of BrS cases, yet ICD implantation is contraindicated or when

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patients experience multiple shocks from their categorized by 2 abnormal QRS waves that
ICD or exhibit supraventricular arrhythmias.91 regularly alternate (Figure 4). Ventricular
Practitioners must advise those with a diagno- tachycardia can result in syncope, ventricular
sis of BrS to avoid drugs known to slow the arrhythmias, cardiac arrest, and sudden car-
function of the sodium channels and poten- diac death, making this a rare but potentially
tially induce ventricular arrhythmias.92 All life-threatening inherited channelopathy.94
members of the health care team should talk
about drugs to avoid as part of patient coun- Genetic Testing, Family Screening
seling. provides a list of Genetic testing of individuals suspected
drugs to be avoided.93 of having CPVT is highly recommended.45
The autosomal dominant form of transmis-
Catecholaminergic Polymorphic sion of CPVT involves alteration in the RyR2
Ventricular Tachycardia gene. The autosomal recessive form of CPVT
Catecholaminergic polymorphic ventricu- involves variation in the CASQ2 gene.100 The
lar tachycardia is a channelopathy that can dominant RyR2 form of CPVT occurs in
disrupt normal calcium-channel ionic flow approximately 65% of patients with CPVT,
within the cardiac myocytes of the heart.94 whereas the CASQ2 variant form affects
CPVT typically is diagnosed in younger adults approximately 3% to 5% of individuals.45,71
(< 40 years old), with a primary onset between Genetic testing of patients in whom CPVT was
age 7 to 12 years in patients who have a struc- diagnosed clinically has a positive mutation
turally normal heart.71,95 yield rate of approximately 65%.98,101 Other
Approximately 1 in 10 000 individuals is genes also have been suspected to be involved
affected by CPVT,71 which is characterized in a similar expression of CPVT; however,
by catecholamine-induced episodic syncope, details of their involvement are evolving.102,103
ventricular tachycardia, and sudden cardiac Genetic testing is required to confirm the
death, typically occurring during physical diagnosis of CPVT.101 Once a pathogenic
exercise or emotional stress95-97 when arrhyth- variation related to CPVT is identified, first-
mias usually are triggered by release of cate- degree and second-degree relatives of the
cholamines (ie, epinephrine, norepinephrine, proband should be assessed genetically and
and dopamine). CPVT has an extraordinarily clinically by cardiac stress testing to see if
high incidence of lethal ventricular arrhythmias the release of catecholamines results in induced
and sudden cardiac death, with a mortality rate ventricular arrhythmias.45 Stress testing is used
of up to 30% in undiagnosed and untreated because physical exercise promotes the release
patients younger than 40 years.98,99 Up to one- of catecholamines that may result in premature
third of patients with CPVT have experienced ventricular complexes that develop, in turn,
at least 1 cardiac arrest in their lifetime.95 into bidirectional or polymorphic ventricular
tachycardia.45 In instances when patients are
Electrocardiogram Characteristics unable to undergo regular stress testing because
Patients with CPVT typically have a nor- of orthopedic issues or other conditions that
mal resting ECG; however, physical exertion restrict mobility, a catecholamine-induced
or emotional stress can alter their baseline drug challenge using epinephrine or isopro-
ECG. These changes may include premature terenol can simulate exercise.71 The practitioner
ventricular complexes, nonsustained ventric- should understand that screening is a funda-
ular tachycardia, and ventricular fibrillation. mental part of the identification of at-risk
The ECG can be used in combination with individuals who may have CPVT.
family history, clinical presentation, and genetic
testing to help confirm a diagnosis of CPVT.71 Treatment for CPVT
The ECG of an individual with CPVT typi- After receiving a diagnosis and counseling,
cally shows a normal sinus rhythm at rest patients should be prescribed an appropriate
with no abnormalities. However, during an β-blocker to lower the risks of future arrhyth-
exercise stress test97 or in the setting of an mic episodes significantly. Nadalol is viewed
emotional event, an individual with CPVT as the most effective β-blocker for treating
may exhibit bidirectional ventricular tachy- patients with CPVT.94 Propranolol also is effec-
cardia and polymorphic ventricular tachycar- tive, although β-blockers do not fully protect
dia. Bidirectional ventricular tachycardia is individuals with CPVT from experiencing

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I V1



aVR V4

aVL V5

* * * * * * * * * * * * * * * * * * * * * * *

Figure 4: Electrocardiogram of patient with CPVT during exercise. Asterisks mark polymorphic ventricular
beats. Image courtesy of Dr C van der Werf and
Abbreviation: CPVT, catecholaminergic polymorphic ventricular tachycardia.

arrhythmic events.99 Genetic testing is espe- ARVD/C are PKP2, DSG2, DSP, and DSC2.
cially important for younger children in fami- All 4 genes code for desmosomal proteins,
lies in which a causative CPVT pathogenic which are responsible for cell linkage and
mutation has been identified; medication can proper adhesion and structure within the
be initiated and counseling provided about heart.109-117 One study found that approxi-
avoiding stressful situations.45 mately 70% of families with ARVD/C had
mutations in the PKP2 gene.118 Nurses must
Arrhythmogenic Right understand that ARVD/C can be difficult to
Ventricular Dysplasia/ diagnose based on genetic testing alone;
Cardiomyopathy research has found that variations in the
Arrhythmogenic right ventricular dyspla- PKP2 and DSG2 genes may not necessarily
sia/cardiomyopathy is known for its abnormali- cause the phenotypical expression of
ties in structure and fatty infiltrates, typically ARVD/C.119,120
within the right ventricle,104,105 and is a major ARVD/C may have no initial symptoms
cause of ventricular arrhythmias in patients or no observed ECG or echocardiogram
aged 35 years or younger.106,107 The structural abnormalities until the disease progresses.
abnormalities lead to functional changes and Hallmark findings include right ventricular
thinning of the right ventricle, resulting in dilation with thinning of the right ventricu-
abnormal motion, structure, and conduction lar wall over time, which can result in aneu-
within the heart. Wall motion abnormalities, rysms, cardiac wall abnormalities, entire
dilation, ventricular aneurysms, and increased loss of ventricular function, ventricular
trabeculation in the right ventricle develop arrhythmias, and sudden cardiac death.108
over time.108 ARVD/C results in inflammation ARVD/C is a rare, genetically inherited
and loss of myocytes, which affect proper channelopathy that can result in changes to
electrical conduction.45 the heart’s electrical conduction system, as
Many genes have been linked to ARVD/C well as a cardiomyopathy resulting in struc-
onset. The 4 main genes associated with tural changes and dilation.121

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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 V1
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 Figure 5: Electrocardiogram showing the hallmark
in the right ventricle and therefore has a left finding of an epsilon wave (arrow) that may lead a
bundle branch block pattern.45 practitioner to suspect arrhythmogenic right ventricu-
lar dysplasia/cardiomyopathy. Image courtesy of Dr
Genetic Testing, Family Screening De Voogt and
Typically, ARVD/C is transmitted in an auto-
somal dominant fashion. However, environ- history, and presentation into account, along
mental and genetic factors as well as age may with confirmatory testing, before diagnosing
contribute to variable penetrance among indi- ARVD/C. In this way, genotyping is support-
viduals, even those in the same family.123-125 ive of the clinical presentation of ARVD/C
Other forms of Mendelian inheritance, such in the proband.131
as autosomal recessive, compound heterozy- Overall, genetic testing is recommended for
gosity, and digenic heterozygosity occur with patients when they exhibit 1 or 2 diagnostic
ARVD/C.109,110,119,126-128 Compound heterozygos- criteria (Table 3).132 If a patient has a muta-
ity refers to individuals who possess 2 differ- tion linked to ARVD/C, subsequent genetic
ent disease alleles of a single gene that can testing of family members and relatives is rec-
cause ARVD/C.129 Digenic heterozygosity refers ommended.45 However, testing is not recom-
to a phenomenon by which a person coinher- mended for patients who only have 1 minor
its disease alleles for 2 genes. diagnostic criterion linked to ARVD/C.45
Approximately 33% of ARVD/C genetic Individuals and families are encouraged
variations are false positives.130 Thus, the inter- to be evaluated at a center that has cared for
disciplinary team should exhibit vigilance those with ARVD/C and is experienced in
when ordering genetic testing and interpreting genetic testing and counseling families with
the subsequent results. Given the relatively complex genetic conditions. In addition, imme-
new and developing use of genetic testing for diate family members of a proband may opt
ARVD/C diagnosis, practitioners are advised to be tested and monitored for the develop-
to take the entire patient profile, family ment of ARVD/C.131 Given ARVD/C’s complex

Table 3: Diagnostic Criteria for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Major Diagnostic Criteria Minor Diagnostic Criteria

Magnetic resonance imaging shows thinning of Family history of sudden cardiac death in individuals
right ventricle free wall < 35 years old
Endomyocardial biopsy with fibro/fatty infiltrates Known family history of ARVD/C
Epsilon wave on electrocardiogram Many premature ventricular complexes
QRS interval prolongation > 110 ms Ventricular tachycardia with left bundle branch block
Right ventricle exhibits segmental dilation Inverted T-wave morphology in the V1-V3 leads, with
Localized right ventricle aneurysms no presence of right bundle branch block
Severe dilation of the right ventricle Right ventricular hypokinesis and dilation
Decreased ejection fraction of the right ventricle Moderate right ventricular dilation, with or without
Autopsy or surgery confirmation of ARVD/C decreased right ventricular ejection fraction, with
normal left ventricular functioning

Abbreviation: ARVD/C, arrhythmogenic right ventricular dysplasia/cardiomyopathy. Adapted from Andrews et al.132

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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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