Introduction
Cardiac arrhythmias are associated with high morbidity and mortality.1 Specifically,
malignant arrhythmias are a recognized leading cause of sudden cardiac death (SCD)
in the Western countries. It has been estimated that every day >1000 SCDs occur in
the United States.1, 2 Although structural heart diseases, particularly coronary artery
disease and heart failure,2, 3 are the prevalent underlying causes of cardiac arrhythmias
and SCD, structural alterations are not identified at the postmortem examination in
5% to 15% of patients, increasing up to 40% in subjects aged <40 years.1, 2 The discovery
that, in the absence of structural heart defects, mutations in the genes encoding
for cardiac ion channels and/or associated regulatory proteins can promote arrhythmias
led to the recognition of a new group of inherited arrhythmogenic diseases, accounting
for a significant proportion of the unexplained cases.4 The term cardiac channelopathies
has been used to designate a collection of genetically mediated syndromes, including
long‐QT syndrome (LQTS), short‐QT syndrome (SQTS), Brugada syndrome (BrS), catecholaminergic
polymorphic ventricular tachycardia (CPVT), early repolarization syndrome (ERS), idiopathic
ventricular fibrillation (IVF), and progressive cardiac conduction disease.5 All these
disorders are caused by the dysfunction (loss or gain of function) of specific cardiomyocyte
ion channels, resulting in a disruption of the cardiac action potential (AP).4 Such
electrical abnormalities lead to an increased susceptibility to develop arrhythmias,
syncope, seizures, or SCD, precipitated by episodes of polymorphic ventricular tachycardia
(torsade de pointes [TdP]) or ventricular fibrillation (VF), typically in the presence
of a structurally normal heart.4 Thus, although the term cardiac channelopathies does
not per se imply a genetic origin, it currently coincides with that of inherited cardiac
channelopathies.1, 5
Accumulating recent evidence demonstrated that factors other than genetic mutations
can promote arrhythmias by causing a selective cardiac ion channel dysfunction in
the absence of any structural heart defect. In addition to a well‐recognized list
of drugs directly interfering with cardiac ion channel function,6 immunologic and
inflammatory factors can cause cardiac channelopathies.7, 8 In fact, besides the established
role of cardiac inflammation, often of autoimmune origin, in promoting arrhythmias
in the presence of an autopsy/biopsy‐proven inflammatory cell tissue infiltration,9,
10, 11, 12, 13 it is increasingly recognized that systemically released autoantibodies
and cytokines can be per se arrhythmogenic, regardless of evident histologic changes
in the heart.14, 15, 16 Several arrhythmogenic autoantibodies targeting calcium, potassium,
or sodium channels in the heart have been identified, and the term autoimmune cardiac
channelopathies has been proposed.7 Moreover, evidence exists that inflammatory cytokines,
mainly tumor necrosis factor (TNF)‐α, interleukin‐1, and interleukin‐6, can modulate
expression and/or function of ion channels, both by directly acting on cardiomyocytes8,
17 and/or inducing systemic effects (fever).17 A careful consideration of these, to
date, largely overlooked factors is highly relevant because they are potentially involved
in several unexplained arrhythmias/SCD that are negative for genetic factors.2 In
patients with unexplained cause of death after a comprehensive postmortem genetic
testing of blood/tissue samples (the so‐called “molecular autopsy”), a genetic cause
is demonstrated in no more than ≈30% of cases.2
As such, a novel and more comprehensive classification of cardiac channelopathies
is herein proposed, distinguishing the “classic” inherited forms, related to genetic
mutations, from the acquired forms, including drug‐induced and more recently recognized
autoimmune and inflammatory/fever‐induced cardiac channelopathies (Figure 1). In this
review, we focus on autoimmune and inflammatory/fever‐induced channelopathies and
their emerging impact on arrhythmic risk, providing both basic and clinical perspectives.
Figure 1
Classification of arrhythmogenic cardiac channelopathies. Besides the “classic” inherited
forms of cardiac channelopathies related to genetic mutations, a wider spectrum of
acquired forms includes not only drug‐induced, but also autoimmune and inflammatory/fever‐induced,
cardiac channelopathies.
Clinical Syndromes
From a clinical point of view, cardiac channelopathies have been associated with ventricular
arrhythmias (VAs), including ventricular tachyarrhythmias and VF, atrial fibrillation
(AF), and bradyarrhythmias.
Tachyarrhythmias
Ventricular tachyarrhythmias and SCD
The most severe cardiac channelopathies are those increasing the propensity for VA
and SCD. Among these, the 4 major syndromes are LQTS, SQTS, BrS, and CPVT. More recently
recognized electrocardiographic phenotypes in this group are ERS and IVF. Because
BrS and ERS share several clinical and pathophysiological aspects, including abnormal
J‐waves in the ECG, they are also collectively called “J‐wave syndromes.”5
Long‐QT Syndrome
LQTS is characterized by a prolonged heart rate–corrected QT interval (QTc) on the
ECG, predisposing to life‐threatening VA, particularly TdP.18 Although the cutoff
value for QTc prolongation is traditionally set at 440 ms, it is currently recommended
that only a QTc >99th percentile (ie, 470 ms for men and 480 ms for women) should
be considered abnormally prolonged (and highly abnormal when >500 ms).18 The more
the QTc prolongs, the greater TdP risk, becoming high and extremely high when QTc
>500 and >600 ms, repectively.18, 19 It is noteworthy that QTc prolongation may not
be always manifest in resting conditions, and it is unmasked only after provocative
tests.5
The QT interval in the ECG is a surrogate measure of the average duration of the ventricular
AP.20 Whenever a channel dysfunction induces an increase in the inward Na+ or Ca++
currents and/or a decrease in an outward K+ current, resulting in an inward shift
in the balance of currents, the AP duration (APD) prolongs and, hence, the QT interval.19,
21, 22 Regardless of the specific channelopathy involved, ion channel dysfunctions
resulting in APD prolongation will increase the susceptibility to develop oscillations
at the plateau level (early afterdepolarizations).18 The early afterdepolarizations
combined with differences in APD lengthening across the ventricular wall (transmural
dispersion of depolarization) could trigger ectopic activity that can induce reentrant
arrhythmias, particularly TdP.21 Although frequently self‐terminating, TdP can degenerate
into VF and SCD.18, 19, 22
Such changes can result from a wide spectrum of cardiac channelopathies, both inherited
and acquired, eventually emerging as LQTS.19, 22 Genetic channelopathies are well
recognized as mutations of 17 different genes that have been currently identified
in clinically diagnosed LQTS.19, 23 Mutations can involve genes encoding the channel‐protein
itself or ion channels’ regulatory proteins, resulting in loss of function of one
of the K+ currents or gain of function of the Na+ or Ca++ currents19, 21 (Table 1).
LQTS‐causing mutations have a prevalence of ≈1:2000 in apparently healthy live births.5
LQT1 (KCNQ1, 30%–35%), LQT2 (KCNH2, 20%–25%), and LQT3 (SCN5A, 5%–10%) represent most
of genotype‐positive cases, whereas more recently discovered LQTSs collectively account
for <5%.5, 19
Table 1
Cardiac Channelopathies Associated With LQTS
Cardiac Channelopathies
Gene
Ion Channel/Regulatory Protein
Mechanism
Effect on Ion Current
Inherited forms
Genetic
LQT1
KCNQ1
Kv7.1
Loss‐of‐function mutation
IKs decrease
LQT2
KCNH2
hERG
Loss‐of‐function mutation
IKr decrease
LQT3
SCN5A
Nav1.5
Gain‐of‐function mutation
INa increase
LQT4
ANK2
Ankyrin B
Loss‐of‐function mutation
ICaL and INa increase
LQT5
KCNE1
Mink
Loss‐of‐function mutation
IKs decrease
LQT6
KCNE2
MiRP1
Loss‐of‐function mutation
IKr decrease
LQT7
KCNJ2
Kir2.1
Loss‐of‐function mutation
IK1 decrease
LQT8
CACNA1C
Cav1.2
Gain‐of‐function mutation
ICaL increase
LQT9
CAV3
Caveolin‐3
Gain‐of‐function mutation
INa increase
LQT10
SCN4B
NavB4
Gain‐of‐function mutation
INa increase
LQT11
AKAP9
Yotiao
Loss‐of‐function mutation
IKs decrease
LQT12
SNTA1
α1 Syntrophin
Gain‐of‐function mutation
INa increase
LQT13
KCNJ5
Kir3.4
Loss‐of‐function mutation
IKACH decrease
LQT14
CALM1
Calmodulin‐1
Loss‐of‐function mutation
ICaL increasea
LQT15
CALM2
Calmodulin‐2
Loss‐of‐function mutation
ICaL increasea
LQT16
CALM3
Calmodulin‐3
Loss‐of‐function mutation
ICaL increasea
LQT17
TRDN
Triadin
Loss‐of‐function mutation
ICaL increasea
Acquired forms
Drug inducedb
Antiarrhythmics (class IA‐III)
···
hERGc
Direct channel inhibition (and/or channel trafficking interference)
IKr decreasec
Antimicrobials
···
Antihistamines
···
Psychoactive agents
···
Motility and antiemetic drugs
···
Anticancer drugs
···
Immunosuppressants
···
Autoimmune
Anti‐hERG antibodies (anti‐Ro/SSA)
···
hERG
Direct channel inhibition
IKr decrease
Anti‐Kv1.4 antibodies
···
Kv1.4
Direct channel inhibition
Ito decreasea
Inflammatory
TNF‐α
···
hERG
Channel function inhibition
IKr decrease
···
Kv7.1
Channel function inhibitiond
IKs decrease
···
Kv4.2/Kv4.3
Channel expression decrease
Ito decrease
Interleukin‐1
···
Cav1.2
Channel function enhancement
ICaL increase
···
Kv4.2/Kv4.3
Channel function inhibitiond
Ito decrease
Interleukin‐6
···
Cav1.2
Channel function enhancement
ICaL increase
Anti‐Ro/SSA indicates anti‐Ro/Sjogren’s syndrome‐related antigen A; hERG, human ether‐a‐go‐go‐related
gene K+‐channel; ICaL, L‐type calcium current; IK1, inward rectifier K+‐current; IKAch,
acetylcholine‐activated current; IKr, rapid component of the delayed rectifier potassium
current; IKs, slow component of the delayed rectifier potassium current; INa, sodium
current; Ito, transient outward potassium current; LQTS, long‐QT syndrome; MiRP, MinK
related protein 1; TNF‐α, tumor necrosis factor‐α.
a
Proposed, because no direct evidence is currently available.
b
A more comprehensive, detailed, and frequently updated list of QT‐prolonging drugs
is available at the website ( https://www.crediblemeds.org).
c
Although hERG inhibition with IKr decrease is the mechanism involved in most cases,
some drugs can inhibit other potassium currents (Ito, IKs, or IK1) or augment sodium
or calcium currents (INa or ICaL).
d
No data on channel expression are currently available.
Besides inherited forms, 3 types of acquired cardiac channelopathies associated with
LQTS exist (ie drug induced,6 autoimmune,7, 17, 24 and inflammatory8, 17, 25) (Table 1).
However, these forms are, to date, largely overlooked or not classified as a channelopathy.
For drugs, a wide range of structurally unrelated medications are known to cause acquired
LQTS, mostly as the result of a direct human ether‐a‐go‐go‐related gene K+‐channel
(hERG) blockade.6 The long list of drugs primarily includes antiarrhythmics, antimicrobials,
antihistamines, and psychoactive drugs (Table 1), and it is continuously increasing
( http://www.crediblemeds.org).6 The other acquired forms of LQTS have received less
attention, probably because they have been only recently characterized.7, 17
To date, 2 LQTS‐induced autoimmune channelopathies have been identified, both associated
with inhibiting autoantibodies cross‐reacting with specific K+ channels (ie, hERG)26,
27, 28 and Kv1.429, 30) (Table 1). Anti‐Ro/SSA antibodies (including anti‐Ro/SSA (anti‐Ro/Sjogren’s
syndrome‐related antigen A) 52‐kD and anti‐Ro/SSA 60‐kD subtypes) can be the cause
of a novel form of acquired LQTS via cross‐reaction and blockade of the hERG‐K+ channel
(Table 1).7, 26, 31 Anti‐Ro/SSA antibodies are reactive with the intracellular soluble
ribonucleoproteins Ro/SSA antigen and are among the most frequently detected autoantibodies
in several connective tissue diseases and in the general, otherwise healthy, population.31,
32 Patients (and their newborns) with anti‐Ro/SSA‐positive connective tissue disease
commonly show QTc prolongation, correlating with autoantibody levels (particularly
anti‐Ro/SSA 52‐kD) and complex VA.31, 33, 34, 35, 36, 37 Moreover, anti‐Ro/SSA 52‐kD
antibodies significantly inhibit the rapid activating component of the delayed K+
currents (IKr), via a direct binding with the extracellular loop between segments
S5 and S6 of the pore‐forming hERG‐channel subunit, where homology with the Ro/SSA
52‐kD antigen is present.26, 27, 28 In addition, immunization of guinea pigs with
a 31–amino acid peptide corresponding to a portion of this extracellular region of
the hERG channel induced antibodies that inhibited IKr and caused APD and QTc prolongation,
in the absence of any cardiac inflammation.16 Some authors did not find a significant
(frequently near‐significant) association between anti‐Ro/SSA and QTc prolongation
in patients with autoimmune diseases,38, 39 and even in studies in which an association
has been demonstrated, the rate of QTc prolongation varied significantly, from 10%
to 60%.37 Besides substantial differences in circulating levels of pathogenic anti‐Ro/SSA
52‐kD among the cohorts, recent evidence from simulation and clinical studies supports
the hypothesis that a concomitant inhibitory effect of anti‐Ro/SSA on L‐type Ca2+
channels can partially counteract IKr inhibition–dependent prolongation of APD, and
the resulting QTc duration on ECG.31 In particular, because IKr is activated after
the peak of the T wave, Tufan et al40 demonstrated that the Tpeak‐Tend interval on
ECG, a recognized independent predictor of SCD in the general population, is significantly
prolonged in patients with anti‐Ro/SSA 52‐kD–positive connective tissue diseases,
also in those patients in whom the QTc was found normal. Besides patients with connective
tissue diseases, anti‐Ro/SSA antibodies are also present in up to ≈3% of the general
population,32 where they could significantly contribute to SCD risk.28 Indeed, anti‐Ro/SSA
52‐kD antibodies exerting hERG‐blocking properties were frequently found (60%) in
unselected patients with TdP, mainly without manifest ADs.28 However, no population
data are currently available on the percentage of anti‐Ro/SSA 52‐kD carriers who actually
manifest the channelopathy and/or develop arrhythmias.
Although less investigated, another form of LQTS‐inducing autoimmune channelopathy
may be related to anti–Kv1.4‐K+ channel antibodies, detected in ≈10% to 20% of patients
with myasthenia gravis.29, 30 The Kv1.4 channel conducts a transient K+‐outward current
(Ito) chiefly determining the early repolarization phase of the AP.20 Anti–Kv1.4‐positive
subjects frequently showed QTc prolongation (≈15%–35%)29, 30 and significant mortality
for lethal QT‐associated arrhythmias (20% of cases).30 Although pathophysiological
studies are currently missing, LQTS seems to result from an autoantibody‐dependent
Ito inhibition, via direct channel binding (Table 1).7, 29, 30 Nevertheless, because
signs of myocarditis are present in a fraction of anti–Kv1.4‐positive patients with
myasthenia gravis,29, 30 it is possible that inflammatory mechanisms and structural
heart changes may contribute to the pathogenesis of electric alterations.
Finally, agonist‐like autoantibodies specifically interacting with the L‐type Ca++
channels were detected in ≈5% to 50% of patients with cardiomyopathies (both idiopathic
dilated cardiomyopathy and ischemic cardiomyopathy) and were associated with an increased
risk of life‐threatening VA/SCD.41, 42 Experimental studies suggest that these autoantibodies,
by directly recognizing an intracellular sequence at the N‐terminus of the Cav1.2
subunit, can increase L‐type inward Ca++ current (ICaL), prolong APD, and result in
early afterdepolarizations and VA.41, 43 Although these data anticipate LQTS as the
associated clinical phenotype, eventually promoting early afterdepolarization–induced
VA and SCD, a specific investigation of QT‐interval behavior in these patients is
substantially missing, thus currently precluding this labelling.
Inflammatory channelopathies are related to systemically or locally released inflammatory
cytokines (mainly TNF‐α, interleukin‐1, and interleukin‐6) able to directly affect
the expression and/or function of several cardiac ion channels, resulting in a decrease
of K+ currents (IKr, Ito, or the slow activating components of the delayed K+ current
[IKs]) and/or an increase of ICaL (Table 1).8, 17 Cardiac or systemic inflammation
promotes QTc‐interval prolongation via cytokine‐mediated effects (Table 1), and this
may increase SCD risk.8, 17 This is supported by several studies in patients with
inflammatory heart diseases, autoimmune inflammatory diseases, infections and apparently
healthy subjects with low‐grade chronic systemic inflammation.8, 44, 45, 46, 47, 48
Thus, regardless of its origin, inflammation per se seems to represent a risk factor
for LQTS and life‐threatening VA. Accordingly, in unselected patients with TdP, C‐reactive
protein (CRP) and interleukin‐6 levels are commonly increased, in ≈50% of subjects
associated with a definite inflammatory disease (infective/immune mediated/other).25
Moreover, in patients with elevated CRP from different inflammatory conditions, QTc
prolongation is common, and CRP reduction associates with a significant QTc shortening,
also correlating with TNF‐α/interleukin‐6 decrease.25, 49 QTc length and reversal
of inflammation‐driven QTc changes directly correlate with cytokine levels,25, 44,
49, 50 suggesting direct functional effects on cardiac electrophysiological properties.
Indeed, inflammatory cytokines prolong ventricular APD by inducing dysfunction of
several cardiac ion channels, particularly K+ channels (Table 1).8, 17 TNF‐α significantly
reduces several K+ currents, including Ito,51, 52, 53, 54 IKr,55, 56 IKs,56 and the
ultrarapid activating component of the delayed K+ currents,51, 54 as a result of an
inhibition of channel (Kv4.2, Kv4.3, or Kv1.5)51, 52, 53, 54 or channel‐interacting
protein56 expression and/or alterations in channel‐gating kinetics.54 Reactive oxygen
species production, nuclear factor‐κB, and asphingomyelin pathway activation seem
to have an important role.53, 55, 56 Consistent APD‐prolonging effects are also exerted
by interleukin‐1, by both reducing Ito
57 and increasing ICaL via a lipoxygenase pathway,58 and interleukin‐6, by phosphorylation
of the 1829‐serine residue of the Cav1.2 subunit, leading to ICaL enhancement.59
Evidence also exists that fever can trigger LQTS and related arrhythmias,60, 61 particularly
in preexisting IKr defects, either genetic or acquired,60 by influencing temperature‐sensitive
biophysical properties of the hERG channel.62 Given the previously described K+ current–inhibiting
effects of cytokines during febrile inflammatory diseases, these molecules could synergistically
work along with temperature in promoting LQTS‐inducing channelopathies.
Short‐QT Syndrome
SQTS is a clinical entity characterized by an abnormally abbreviated QTc associated
with a high incidence of life‐threatening VA and SCD, but also atrial arrhythmias,
particularly AF.5 Although diagnostic QTc values are still debated, a cutoff of QTc
<360 ms is currently suggested.5 From an electrophysiological point of view, SQTS
is associated with a heterogeneous APD abbreviation, mostly in the epicardium, leading
to an increased transmural dispersion of repolarization that promotes reentrant excitation.21
Dispersion of repolarization operating in both ventricular and atrial myocardium underlies
the susceptibility of patients with SQTS to VA and AF.21, 63
Shortening of APD causing SQTS could result from any cardiac channelopathy leading
to an increase in one of the repolarizing outward K+ currents and/or a decrease in
the inward Na+ or Ca++ currents, resulting in an outward shift in the balance of currents21
(Table 2). Although inherited channelopathies are the most recognized, acquired channelopathies
associated with SQTS have been recently described, including drug‐induced and autoimmune
forms7, 64 (Table 2).
Table 2
Cardiac Channelopathies Associated With SQTS
Cardiac Channelopathies
Gene
Ion Channel
Mechanism
Effect on Ion Current
Inherited forms
Genetic
SQT1
KCNH2
hERG
Gain‐of‐function mutation
IKr increase
SQT2
KCNQ1
Kv7.1
Gain‐of‐function mutation
IKs increase
SQT3
KCNJ2
Kir2.1
Gain‐of‐function mutation
IK1 increase
SQT4
CACNA1C
Cav1.2
Loss‐of‐function mutation
ICaL decrease
SQT5
CACNB2
Cavβ2b
Loss‐of‐function mutation
ICaL decrease
SQT6
CACNA2D1
Cavα2δ
Loss‐of‐function mutation
ICaL decrease
Acquired forms
Drug induced
Rufinamide (antiepileptic)a
···
Nav1.5
Direct channel inhibition
INa decrease
Lamotrigine (antiepileptic)a
···
Nav1.5
Direct channel inhibition
INa decrease
Cav1.2
Direct channel inhibition
ICaL decrease
Nicorandil (antianginal)
···
Kir6.2
Direct channel activation
IKATP increase
Levcromakalim (vasodilator)
···
Kir6.2
Direct channel activation
IKATP increase
Autoimmune
Anti‐Kv7.1 antibodies
···
Kv7.1
Direct channel activation
IKs increase
hERG indicates human ether‐a‐go‐go‐related gene K+‐channel; ICaL, L‐type calcium current;
IK1, inward rectifier K+‐current; IKATP, adenosine triphosphate‐sensitive current;
IKr, rapid component of the delayed rectifier potassium current; IKs, slow component
of the delayed rectifier potassium current; INa, sodium current; SQTS, short‐QT syndrome.
a
Mechanisms of action of these drugs are proposed, because no direct evidence is currently
available.
Genetic SQTS is extremely rare (<200 cases worldwide),63 with 6 identified causative
genes. SQT1, SQT2, and SQT3 are attributable to gain‐of‐function mutations of 3 different
K+ channel–encoding genes increasing repolarizing currents, whereas SQT4, SQT5, and
SQT6 are induced by loss‐of‐function mutations in genes encoding L‐type Ca++ channel
subunits, all decreasing the ICaL‐depolarizing current5, 21, 63 (Table 2). The recommendations
on genetic SQTS diagnosis are based on QTc duration, personal/family history, and
genetic testing,5 although the overall yield of genetic screening in patients with
SQTS is still low (≈15%–20%).63 Thus, although further causative genes are expected
to be identified in the future,63 a potential role for acquired channelopathies (Table 2)
in several patients with SQTS should be considered.
Some drugs, including specific antiepileptic, antianginal, and vasodilator drugs (http://www.crediblemeds.org),
can induce QTc shortening by directly interfering with specific cardiac ion channels,
mainly decreasing the inward Na+ current (INa) or increasing the acetylcholine‐activated
K+ current64 (Table 2). However, at present, there is little proof of QT‐shortening
drugs causing VF in humans in no more than rare isolated instances.64
An autoimmune cardiac channelopathy leading to SQTS has recently been described in
patients with dilated cardiomyopathy,65 associated with Kv7.1 channel–targeting agonist‐like
autoantibodies increasing IKs
15, 65 (Table 2). These autoantibodies, reacting with the S5 to S6 pore region, were
demonstrated in patients with dilated cardiomyopathy with shortened QTc.65 Although
no direct data with purified autoantibodies are currently available, it is likely
that anti‐Kv7.1 antibodies enhance IKs by exerting an agonist‐like effect on the channel.
In fact, patient serum containing anti‐Kv7.1 antibodies increased IKs density in human
embryonic kidney 293 cells expressing KCNQ1/KCNE1 genes, and APD was shortened as
a result of an increase in IKs in cardiomyocytes isolated from rabbits immunized with
the Kv7.1 channel pore‐peptide.15, 65 Moreover, immunized animals showed QTc shortening,
reduced ventricular effective refractory periods, and markedly increased vulnerability
to VA.15 Notably, these changes occurred in the presence of extensive antibody deposition
within the myocardium, but without echocardiography modifications or histologic evidence
of myocardial leukocyte infiltration or fibrosis.15
Brugada Syndrome
BrS is a channelopathy associated with a high incidence of SCD in a structurally normal
heart, characterized by a peculiar ECG phenotype with accentuated J‐waves leading
to ST‐segment elevation in right precordial leads.4, 5, 66 Three ECG patterns exist:
type 1 (“coved type”), type 2 (“saddle‐back type”), and type 3.21 The prevalence of
BrS ranges from 5 to 20 cases/10 000 subjects worldwide, being particularly high in
Asia. After car accidents, BrS is the leading cause of death in subjects aged <40 years,
particularly men.4, 5, 67
BrS is primarily recognized as a genetic channelopathy.21 To date, mutations in 19
genes have been identified, in all cases leading to an outward shift in the balance
of currents during the AP early phases as a result of a decrease in the inward Na+
or Ca++ currents or an increase in an outward K+ current21 (Table 3). Mutations in
the Nav1.5‐encoding SCN5A gene account for >75% of BrS genotype‐positive cases, although
the yield of SCN5A testing for clinical cases is only ≈25% to 30%.5 In the presence
of the previously described changes in ion currents, particularly INa reduction, the
net repolarizing effect of Ito during phase 1 is significantly enhanced, thus reducing
cell voltage to values below those required to activate L‐type Ca++ channels. Such
an effect, mainly evident in the subepicardial cells of the right ventricular outflow
tract (RVOT), where Ito is prominent, reduces Ca++‐channel activation with a loss
in the AP plateau. This accentuates the AP notch in the right ventricular epicardium
relative to the endocardium, generating a transmural voltage gradient responsible
for abnormal J‐waves in the right precordial leads.21, 67 Conduction of the AP dome
from epicardial sites, where it is conserved, to sites where it is lost results in
reentrant excitation (phase 2 reentry) and VT/VF.21 In this repolarization hypothesis,
the evidence that an SCN5A‐promoter polymorphism slowing cardiac conduction is common
in Asians, and that men present a more prominent Ito current, may help explain racial
and sexual differences.5, 67 Besides repolarization abnormalities, many experimental
data suggest that a slowed conduction in the RVOT is also involved in BrS‐related
ECG and arrhythmogenesis.67 According to this depolarization hypothesis, the AP of
the RVOT is delayed with respect to the AP of the right ventricle, and this potential
gradient contributes to ST‐segment elevation. The underlying mechanism seems to be
a lower “conduction reserve” related to a particularly low RVOT expression of SCN5A,
but also of connexin 43 (or gap junction‐α1 protein) with abnormal gap‐junctional
communication.67 In addition, regulating effects on INa amplitude are recently documented
as additional noncanonical functions of connexin 43.68 Such an expression pattern,
characteristic of the embryonic heart and physiologically retained in the adult RVOT,
would be markedly accentuated in patients with BrS.67 Accordingly, a genetically reduced
Na+‐channel function unmasks slow conduction in RVOT.67 Moreover, a recent postmortem
study found that connexin 43 expression is reduced in RVOT of patients with BrS and
correlated with abnormal APs.69
Table 3
Cardiac Channelopathies Associated With BrS
Cardiac Channelopathies
Gene
Ion Channel/Regulatory Protein
Mechanism
Effect on Ion Current
Inherited forms
Genetic
BrS1
SCN5A
Nav1.5
Loss‐of‐function mutation
INa decrease
BrS2
GPD1L
Glycerol‐3‐phosphate dehydrogenase 1‐like
Loss‐of‐function mutation
INa decrease
BsS3
CACNA1C
Cav1.2
Loss‐of‐function mutation
ICaL decrease
BsS4
CACNB2
Cavβ2b
Loss‐of‐function mutation
ICaL decrease
BrS5
SCN1B
Navβ1
Loss‐of‐function mutation
INa decrease
BrS6
KCNE3
MiRP2
Gain‐of‐function mutation
Ito increase
BrS7
SCN3B
Navβ3
Loss‐of‐function mutation
INa decrease
BrS8
KCNJ8
Kir6.1
Gain‐of‐function mutation
IKATP increase
BrS9
CACNA2D1
Cavα2δ
Loss‐of‐function mutation
ICaL decrease
BrS10
KCND3
Kv4.3
Gain‐of‐function mutation
Ito increase
BrS11
RANGRF
MOG1
Loss‐of‐function mutation
INa decrease
BrS12
SLMAP
Sarcolemmal membrane‐associated protein
Loss‐of‐function mutation
INa decrease
BrS13
ABCC9
SUR2A
Gain‐of‐function mutation
IKATP increase
BrS14
SCN2B
Navβ2
Loss‐of‐function mutation
INa decrease
BrS15
PKP2
Plakophillin‐2
Loss‐of‐function mutation
INa decrease
BrS16
FGF12
FAHF1
Loss‐of‐function mutation
INa decrease
BrS17
SCN10A
Nav1.8
Loss‐of‐function mutation
INa decrease
BsS18
HEY2
Hey2‐encoded transcription factor
Gain‐of‐function mutation
INa increase
BrS19
SEMA3A
Semaphorin
Gain‐of‐function mutation
Ito increase
Acquired forms
Drug induced*
Antiarrhythmics (class IA‐IC)
···
Nav1.5
Direct channel inhibition
INa decrease
Psychoactive agents†
···
Anesthetics/analgesics†
···
Antiepileptics
···
Antihistamines†
···
Potassium channel openers
···
Kir6.1/Kir6.2
Direct channel activation
IKATP increase
Calcium channel blockers
···
Cav1.2
Direct channel inhibition
ICaL decrease
Fever induced
Fever
···
Nav1.5
Channel biophysical properties modification
INa decrease
BrS indicates Brugada syndrome; FAHF1, fibroblast‐growth factor homologous factor‐1;
ICaL, L‐type calcium current; IKATP, adenosine triphosphate‐sensitive current; INa,
sodium current; Ito, transient outward potassium current; SUR2A, sulfonylurea receptor
2A.
*A more comprehensive, detailed, and frequently updated list of drugs is available
at https://www.brugadadrugs.org.
†Some of the drugs included in these categories inhibit both sodium and calcium channels.
The BrS‐ECG phenotype is often concealed and unmasked by several acquired factors,
both endogenous (eg, fever, vagotonic maneuvers, and electrolyte disturbances) and
environmental (eg, drugs and toxic agents66 [ http://www.brugadadrugs.org]). The role
of class IC and IA antiarrhythmics and fever seems particularly important.5, 66 Current
recommendations require that the type 1 pattern, whether spontaneous or induced by
Na+‐channel blockers or fever, is present for the diagnosis of BrS. However, a provoked
type 1 pattern alone is not sufficient without specific clinical or familial features.66
Other acquired factors, partly overlapping those unmasking true genetic BrS (eg, electrolyte
imbalances), can lead to a similar/identical ECG pattern in predisposed subjects,
in the absence of any apparent genetic dysfunction.66 Metabolic conditions, mechanical
compression, myocardial ischemia and pulmonary embolism, and myocardial and pericardial
diseases are included. These conditions, termed Brugada phenocopies, are thought to
result from any acquired factor directly or indirectly increasing outward K+ currents
and/or decreasing inward INa or ICaL. However, the appropriateness of this terminology
is highly debated, not only because the prerequisite of a genetic component is difficult
to rule out,66 but also because fever‐ or drug‐induced type I pattern prevalence in
the general population is relatively high, thus not being particularly specific.70,
71, 72 This could be related to genetic polymorphisms rather than disease‐causing
mutations,70 as recognized for drug‐induced LQTS.6, 18 Thus, current experts’ opinion
is that, in the absence of further genetic or familial features, designating all these
conditions as acquired forms of BrS may be more appropriate and better aligned with
the terminology used for the LQTS.66 Accordingly, drugs and fever are herein specifically
recognized as inducers of BrS‐associated acquired cardiac channelopathies (ie, potential
causes of acquired BrS) (Table 3). Medications inducing BrS include class IA to IC
antiarrhythmics and other Na+‐channel blockers, such as psychoactive agents, anesthetics/analgesics,
antiepileptics and antihistamines, as well as Ca++‐channel blockers and K+‐channel
openers.6
Fever is a well‐recognized acquired factor unmasking BrS in predisposed subjects.66
Although data on large populations are currently lacking, recent studies suggest that
fever‐induced BrS might have a higher than expected prevalence in the general population,70,
72 also possibly associating with a significant risk of arrhythmic events.73 Similarly
to drug‐induced BrS/LQTS, fever‐induced BrS is probably an acquired channelopathy
whose ECG/clinical consequences emerge only in the presence of a latent ion channel
dysfunction.70 Biophysical properties of the Nav1.5 channel are significantly altered
by high temperature, resulting in INa decrease.74, 75 Thus, in febrile conditions,
any subject with a preexisting Na+‐channel impairment could develop an acquired BrS.65
Independent of occult SCN5A disease‐causing mutations, demonstrated in ≈15% to 25%
of tested cases,73 common SCN5A polymorphisms may play an important predisposing role.70
Besides genetics, also acquired factors, particularly drugs, may cause a latent ion
channel dysfunction.70, 76 The biophysical mechanisms in fever‐induced BrS are supported
by the evidence that warm water instillation into the epicardial space can mimic fever
effect.77 In addition, cytokines might intriguingly contribute to fever‐induced BrS,
possibly by decreasing cardiac connexin 43 expression.67, 69 Indeed, increasing evidence
points to systemic and/or cardiac inflammation as a novel factor potentially involved
in BrS pathogenesis.78, 79, 80 Because the key mediators of the fever (ie, inflammatory
cytokines) are also able to rapidly decrease ventricular expression of connexin 4381,
82, 83 and thereby the conduction reserve, it is possible to speculate that during
febrile states not only high temperature but also the inflammatory process may per
se promote acquired BrS via cytokine‐mediated effects on gap‐junction channels.
Catecholaminergic Polymorphic Ventricular Tachycardia
CPVT is a rare inherited channelopathy characterized by adrenergic‐induced bidirectional
or polymorphic VT or VF. Although the estimated prevalence is ≈0.1/10 000, the real
frequency in the general population is unknown because the resting ECG is often unremarkable.5,
84 Most patients experience arrhythmias before the age of 40 years, in one third of
cases in individuals aged <10 years, and mortality is high in untreated subjects.78
Typical presentations include either stress‐induced syncope or cardiac arrest/SCD,
as a result of polymorphic VA induced by adrenergic stimuli (exercise or emotions).
The hallmark of CPVT is the so‐called bidirectional VT, a peculiar polymorphic VT
characterized by a 180° beat‐to‐beat rotation of the ectopic QRS complexes, highly
specific but not always present.84 Other common ECG findings comprise stress‐induced
supraventricular arrhythmias, including AF, as well as sinus bradycardia and prominent
U waves in resting conditions.5, 84
Five different genes have been associated with CPVT encoding the ryanodine receptor‐2
(RyR2), a Ca++‐release channel located in the sarcoplasmic reticulum (SR) membrane,
or RyR2‐regulatory protein, particularly calsequestrin‐2 (CASQ2), calmodulin, triadin,
and trans‐2,2‐enoyl‐CoA reductase‐like protein (Table 4).23 CPVT1 (RyR2, 60%–65%)
and CPVT2 (CASQ2, 3%–5%) alone explain about two thirds of genotype‐positive patients.23,
84 In all cases, mutations eventually result in an RyR2 malfunction leading to spontaneous
Ca++ leakage from SR in diastole, particularly during intense adrenergic activation
(which physiologically increases Ca++ release from the SR).23 The subsequent Ca++
overload is thought to cause delayed afterdepolarizations by activating the Na+/Ca++
exchanger, which generates a Ca++‐dependent transient‐inward depolarizing current,
in turn triggering both ventricular and atrial tachyarrhythmias.4, 21, 23, 84 An alternating
activation of the Purkinje fibers in the 2 ventricles seems to be the electrophysiological
mechanism responsible for bidirectional VT.21, 84
Table 4
Cardiac Channelopathies Associated With CPVT and ERS
Cardiac Channelopathies
Gene
Ion Channel/Regulatory Protein
Mechanism
Effect on Ion Current
CPVT
Genetic
CPVT1
RYR2
Ryanodine receptor‐2
Gain‐of‐function mutation
Diastolic Ca++ release
CPVT2
CASQ2
Calsequestrin‐2
Loss‐of‐function mutation
Diastolic Ca++ release
CPVT3
TECRL
Trans‐2,3‐enoyl‐CoA‐reductase‐like
Loss‐of‐function mutation
Diastolic Ca++ release
CPVT4
CALM1
Calmodulin‐1
Loss‐of‐function mutation
Diastolic Ca++ release
CPVT5
TRDN
Triadin
Loss‐of‐function mutation
Diastolic Ca++ release
ERS
Genetic
ERS1
KCNJ8
Kir6.1
Gain‐of‐function mutation
IKATP increase
ERS2
CACNA1C
Cav1.2
Loss‐of‐function mutation
ICaL decrease
ERS3
CACNB2
Cavβ2b
Loss‐of‐function mutation
ICaL decrease
ERS4
CACNA2D1
Cavα2δ
Loss‐of‐function mutation
ICaL decrease
ERS5
ABCC9
SUR2A
Gain‐of‐function mutation
IKATP increase
ERS6
SCN5A
Nav1.5
Loss‐of‐function mutation
INa decrease
ERS7
SCN10A
Nav1.8
Loss‐of‐function mutation
INa decrease
CPVT indicates catecholaminergic polymorphic ventricular tachycardia; ERS, early repolarization
syndrome; ICaL, L‐type calcium current; IKATP, adenosine triphosphate‐sensitive current;
INa, sodium current; SUR2A, sulfonylurea receptor 2A.
Besides genetic mutations responsible for CPVT, several acquired factors can induce
bidirectional VT, including drugs, toxins, and inflammatory heart diseases.4, 85 In
particular, bidirectional VT is the prototypical arrhythmia during digitalis intoxication,
although the underlying mechanism is indirect via inhibition of the Na+/K+‐ATPase
pump.4 Some CASQ2‐affinity drugs, such as psychoactive agents (phenothiazines and
tricyclic antidepressants) and cocaine, were shown to accumulate in the SR, leading
to direct RyR2 dysfunction and Ca++ leakage,86, 87 similar to what was observed in
all CPVT‐related CASQ2 mutations. In addition, inflammatory cytokines can directly
increase diastolic Ca++ release and arrhythmia susceptibility, also regardless of
structural alterations (eg, myocarditis). TNF‐α and interleukin‐1 were demonstrated
to significantly enhance diastolic Ca++ release by reducing expression and function
of important SR Ca++‐handling proteins,88, 89, 90 including RyR2.91 Whether such drug‐
and inflammatory‐induced channelopathies may represent novel potential forms of acquired
CPVT is speculative at present.
Early Repolarization Syndrome
Early repolarization pattern (ERP) is a frequent ECG phenotype occurring in up to
≈10% of the general population, particularly men and athletes.63, 66 Several studies
suggest that ERP is familial, thereby pointing to underlying genetic contributions.5
A recent expert consensus conference recommended that ERP is recognized in the presence
of the following: (1) a J‐wave, (2) a J‐point elevation, and (3) a normal QRS duration.66
ERP was considered benign until the 2000s, when both experimental and population‐based
clinical studies demonstrated that this pattern, particularly in the inferior and
lateral leads, was associated with an increased incidence of VT/VF and SCD.5, 63,
66 Accordingly, ERS is now exclusively diagnosed in patients showing an ERP in the
inferior and/or lateral leads, presenting with aborted cardiac arrest, documented
VF, or polymorphic VT.5, 66 The evidence that patients with ERP are more susceptible
to VF during myocardial ischemia suggests that this pattern may represent a substrate
increasing SCD risk in the presence of triggers.5, 63
The most accredited theory suggests that ECG features of ERS are secondary to repolarizing
gradients across the ventricular wall.63 Physiologically, epicardium has a higher
Ito, particularly in the left ventricle inferior wall, responsible for a transmural
voltage gradient. Conditions increasing outward K+ currents and/or decreasing inward
INa or ICaL may accentuate such a gradient, resulting in a prominent Ito‐mediated
phase 1 notch of the epicardial AP (responsible for J‐wave and J‐point elevation)
and an increased vulnerability to VAs because of phase 2 reentry.21 In this context,
further accentuation of Ito (eg, during myocardial ischemia) may precipitate VF.5,
63, 66
ERS is considered an inherited channelopathy associated with genetic variants in 7
genes, leading to gain of function of the ATP‐dependent K+ channel or loss of function
of cardiac L‐type Ca++ or Na+ channels66 (Table 4). Nevertheless, the lack of functional/biological
validation of many of these mutations and the high prevalence of ERP in the general
population support the current view that ERS has likely a polygenic basis, also being
influenced by nongenetic factors.5 Several acquired factors are known to cause/modulate
ERP, including acute myocardial injury or infarction, cardiac inflammatory diseases
(possibly via cytokine‐mediated effects),92 Takotsubo cardiomyopathy, left ventricular
hypertrophy, high vagal tone, hypercalcemia, hyperpotassemia, and cocaine.66 Although
to date unproved, the possibility that some of these factors may act by inducing an
acquired channelopathy is conceivable. Intriguingly, a potential role of inflammatory
cytokines is suggested by a recent study that reported that among major league soccer
players, subjects with ERP showed 3‐fold higher circulating interleukin‐6 levels than
those without ERP.92
Idiopathic Ventricular Fibrillation
IVF is a rare cause of sudden cardiac arrest identifying a VF of unknown origin despite
extensive diagnostic testing.5 Thus, the diagnosis of IVF implies the exclusion of
specific diseases, including structural heart diseases and primary arrhythmia syndromes,
such as LQTS, SQTS, BrS, CPVT, and ERS.93
Most of the currently recognized primary arrhythmia syndromes were initially labelled
as IVF (eg, ERS), until recently regarded as a subentity of IVF. In all cases, the
identification of a distinctive ECG phenotype and a separate genetic substrate led
to reclassification of several patients, previously diagnosed as having IVF. As a
result, IVF incidence is progressively declining.93
Although pathogenic mechanisms remain largely unknown, recent data support a genetic
substrate for IVF. Several causative mutations in 4 different genes (DPP6, CALM1,
RyR2, and IRX3) responsible for changes in cardiac ion channels have been detected
in patients with IVF, although it is not currently clear whether the disease is monogenic
or polygenic.93 Notably, most of these mutations have been demonstrated in a subgroup
of patients characterized by short‐coupled ventricular premature beats triggering
TdP/immediate VF. By creating a repolarization gradient with the adjacent ventricular
myocardium promoting phase 2 reentry, a selective Ito increase in Purkinje fibers
may constitute the cellular mechanism for short‐coupled ventricular premature beats
triggering TdP/immediate VF. However, because no ECG phenotype can be detected, to
date, short‐coupled ventricular premature beats triggering TdP/immediate VF remain
a subgroup of IVF.93
An alternative hypothesis is that IVF is multifactorial, resulting from a combination
of monogenic/polygenic mutations and acquired abnormalities, either structural (minimal,
subclinical alterations, currently undetectable with available diagnostic tools) or
functional (eg, electrolyte disturbances or autonomic changes). Among the latter,
it can be speculated that factors known to induce acquired cardiac channelopathies,
but frequently unapparent, such as subclinical autoimmunity and inflammation,7, 8
could also play a role in some patients.
Atrial Fibrillation
AF is the most common sustained arrhythmia in the general population.94 Cardiac diseases,
particularly coronary artery disease, valvular disease, and heart failure, represent
definite risk factors for AF.94 Cardiac channelopathies, both inherited95 and acquired
(inflammation‐induced),96 may generate an electric substrate for this arrhythmia,
in the absence of structural heart defects.
The heritability of AF is supported by many studies in the general population and
twins, and a family history of AF is associated with a 2‐fold risk.95 Moreover, patients
with some specific genetic channelopathies, particularly LQTS, SQTS, BrS, and CPVT,
are at increased risk of AF.5 Accordingly, several gain‐of‐function or loss‐of‐function
mutations in many genes encoding for cardiac ion channels have been described in patients
with early‐onset lone AF or families with autosomal dominant AF95 (Table 5). These
variants, mainly involving K+‐ or Na+‐channel subunits or gap‐junction proteins (connexin
40 or connexin 43), can either shorten or prolong atrial APD and impaired cell‐cell
coupling, leading to intra‐atrial conduction heterogeneity.95 These changes putatively
create a substrate for reentry or increase susceptibility to early and/or delayed
afterdepolarizations, both able to promote AF.95 However, although these variants
have strong effects and a clear phenotype, they are rare, thereby accounting only
for a small proportion of AF (familial monogenic forms). Thus, several genome‐wide
association studies have been performed to identify common genetic variants or single‐nucleotide
polymorphisms.95 Altogether, genome‐wide association studies led to the identification
of >30 AF‐associated loci, mostly involving regulatory sequences presumed to influence
gene expression. Some of these variants are close to ion channels or related proteins
known to regulate the atrial APD (KCNN3, HCN4, and Cav1.2), thereby putatively acting
via channelopathy‐mediated mechanisms.95
Table 5
Cardiac Channelopathies Associated With AF
Gene/Acquired Factor
Ion Channel
Mechanism
Effect on Ion Current
Inherited forms
Genetic
Potassium channels
KCNQ1
Kv7.1
Gain‐of‐function mutation
IKs increase
KCNE1
Mink
Gain‐of‐function mutation
IKs increase
KCNE2
MiRP1
Gain‐of‐function mutation
IKs increase
KCNE5
Kv7.1 (β subunit)
Gain‐of‐function mutation
IKs increase
KCNJ2
Kir2.1 (β subunit)
Gain‐of‐function mutation
IK1 increase
KCNA5
Kv1.5
Gain‐of‐function mutation
IKur modulation
KCNH2
hERG
Gain‐of‐function mutation
IKr modulation
KCND3
Kv4.3
Gain‐of‐function mutation
Ito increase
KCNJ8
Kir6.1
Gain‐of‐function mutation
IKATP increase
KCNN3
KCa2.3
Gain‐of‐function mutation
SKCa modulation
HCN4
Hyperpolarization‐activated cyclic nucleotide–gated potassium channel 4
Gain‐of‐function mutation
If modulation
ABCC9
SUR2A
Gain‐of‐function mutation
IKATP decrease
Sodium channels
SCN5A
Nav1.5
Loss‐of‐function mutation
INa modulation
SCN1B
Navβ1
Loss‐of‐function mutation
INa decrease
SCN2B
Navβ2
Loss‐of‐function mutation
INa decrease
SCN3B
Navβ3
Loss‐of‐function mutation
INa decrease
SCN4B
Navβ4
Loss‐of‐function mutation
NC
SCN10A
Nav1.8
Loss‐of‐function mutation
INa modulation
Calcium channels
RYR2
Ryanodine receptor 2
Gain‐of‐function mutation
Diastolic Ca++ release
Gap‐junction channels
GJA1
Connexin 43
Loss‐of‐function mutation
Intercellular electrical coupling reduction
GJA5
Connexin 40
Loss‐of‐function mutation
Intercellular electrical coupling impairment
Acquired forms
Inflammatory
TNF‐α
Connexin 40
Channel expression decrease
Intercellular electrical coupling reduction
Connexin 43
Channel redistribution
Intercellular electrical coupling impairment
Ryanodine receptor 2
Channel function increase
Diastolic Ca++ release
Interleukin‐1
Cav1.2
Channel expression decrease
ICaL decrease
AF indicates atrial fibrillation; ICaL, L‐type calcium current; IK1, inward rectifier
K+‐current; IKATP, adenosine triphosphate‐sensitive current; IKs, slow component of
the delayed rectifier potassium current; IKur, ultrarapid component of the delayed
rectifier potassium current; INa, sodium current; Ito, transient outward potassium
current; If, funny current; MiRP, MinK related protein 1; NC, not characterized; SKCa,
small‐conductance calcium‐activated potassium channels; SUR2A, sulfonylurea receptor
2A; TNF‐α, tumor necrosis factor‐α.
In most cases, AF may result from a complex combination of genetic and acquired risk
factors.94 In particular, a key role for inflammation, either cardiac or systemic,
in the pathophysiology of AF is largely supported.96 Several studies associate CRP
and inflammatory cytokine levels (mainly TNF‐α and interleukins 1, 2, and 6) with
the presence/outcome of AF.96 Although sustained inflammation is associated with atrial
structural remodeling, several data indicate that inflammatory cytokines can also
directly induce significant changes in the electrical properties of the atrium, already
in the short‐term, thereby independent of any structural alteration.8, 96 In fact,
mounting evidence points to TNF‐α and interleukin‐1 as mediators of acquired atrial
channelopathies, leading to an increased susceptibility to AF (Table 5). Specifically,
these cytokines are able to enhance propensity to delayed afterdepolarizations promoting
ectopic activity97, 98 and to slow atrial conduction, creating a vulnerable substrate
for reentry.99, 100, 101 TNF‐α and interleukin‐1 significantly increase spontaneous
diastolic SR Ca++ leak in cardiomyocytes by impairing RyR2 or related SR Ca++‐handling
proteins.88, 89, 90, 91 In atrial myocytes, TNF‐α seems to act97, 98 via a reactive
oxygen species pathway, increasing Ca++/calmodulin‐dependent protein‐kinase II–dependent
RyR2 phosphorylation.98 TNF‐α can also induce gap‐junction channel dysfunction via
impaired atrial connexin 40 and connexin 43 expression and/or distribution,99, 100,
101 thus favoring a slow and heterogeneous conduction in the atria. Similar effects
on Ca++ handling89, 90, 91 and connexins81, 82, 83 can also be induced in ventricles
by interleukin‐1. In addition, by inducing an L‐type Ca++ channelopathy, interleukin‐1
can shorten the atrial effective refractory period, thereby creating a further substrate
for reentry.101 Other cytokine‐induced channelopathies in atrial cardiomyocytes involve
(T)‐type Ca++ channel (TNF‐α–mediated Cav3.1/Cav3.2 downregulation with transient
inward Ca++‐current (ICaT) decrease)102 and Na+ channel (interleukin‐2–mediated cardiac
Na+‐channel β3‐subunit upregulation with INa increase),103 although mechanistic links
with AF are merely speculative.
Bradyarrhythmias
Bradyarrhythmias, including sinoatrial (SA) node dysfunction and AV‐conduction defects,
frequently occur in the clinical practice.104 Characteristic ECG findings include
persistent sinus bradycardia, SA block, sick‐sinus syndrome, prolonged P‐wave duration,
AV block, and QRS widening with axis deviation.5 Bradyarrhythmias may be either physiological
(ie, in athletes) or pathological.104 Although structural cardiac diseases eventually
leading to sclerosis of the conduction system account for most of the latter forms,
bradyarrhythmias may also occur in a structurally normal heart as a result of inherited
or acquired cardiac channelopathies.5, 7, 105 Several ion channels critically involved
in pace‐making cells’ automaticity and/or AP propagation throughout the conduction
system may be affected (ie T‐ and L‐type Ca++ channels, Na+ channel, hyperpolarization‐activated
cyclic nucleotide–gated channels [HCN4], transient receptor‐potential cation‐channel
subfamily melastatine member‐4 [TRPM4] channel, and gap‐junction channels5, 105, 106)
(Table 6).
Table 6
Cardiac Channelopathies Associated With Bradyarrhythmias
Gene/Acquired Factor
Ion Channel
Mechanism
Effect on Ion Current
Clinical Phenotype
Inherited forms
Genetic
SCN5A
Nav1.5
Loss‐of‐function mutation
INa decrease
SSS, SAN exit block, AVB, PCCD
TRPM4
TRPM4
Loss‐of‐function mutation/gain‐of‐function mutation
Nonselective cation current changes
Sinus bradycardia, PFHB I, PCCD
HCN4
Hyperpolarization‐activated cyclic nucleotide–gated potassium channel 4
Loss‐of‐function mutation
If decrease
Sinus bradycardia
CACNA1D
Cav1.3
Loss‐of‐function mutation
ICaL decrease
Sinus bradycardia, AVB
SCN1B
Navβ1
Loss‐of‐function mutation
INa decrease
Sinus bradycardia, AVB
GJA5
Connexin 40
Loss‐of‐function mutation
Intercellular electrical coupling reduction
PFHB I
GJC1
Connexin 45
Loss‐of‐function mutation
Intercellular electrical coupling impairment
PCCD
Acquired forms
Drug induced
Antiarrhythmics (class I)
Nav1.5
Direct channel inhibition
INa decrease
Sinus bradycardia, AVB
Amiodarone
Cav1.2
Direct channel inhibition
ICaL decrease
Sinus bradycardia AVB
Nav1.5
Direct channel inhibition
INa decrease
Calcium channel blockers
Cav1.2
Direct channel inhibition
ICaL decrease
Sinus bradycardia, AVB
Ivabradine
Hyperpolarization‐activated cyclic nucleotide–gated potassium channel 4
Direct channel inhibition
If decrease
Sinus bradycardia
Lithium
Nav1.5
Direct channel inhibition
INa decrease
Sinus bradycardia, AVB
Phenytoin
Nav1.5
Direct channel inhibition
INa decrease
Sinus bradycardia, AVB
Autoimmune
Anti–L‐type calcium channel antibodies (anti‐Ro/SSA)
Cav1.2/Cav1.3
Direct channel inhibition
ICaL decrease
Sinus bradycardia, AVB
Anti–T‐type calcium channel antibodies (anti‐Ro/SSA)
Cav3.1/Cav3.2
Direct channel inhibition
ICaT decrease
Sinus bradycardia, AVB
Anti–sodium channel antibodies
Nav1.5
Direct channel inhibition/channel expression reduction
INa decrease
Sinus bradycardia, AVB
Anti‐Ro/SSA indicates anti‐Ro/Sjogren’s syndrome‐related antigen A; AVB, AV block;
ICaL, L‐type calcium current; ICaT, T‐type calcium current; If, funny current; PCCD,
progressive cardiac conduction disease; PFHB I, progressive familial heart block I;
SAN, sinoatrial node; SSS, sick sinus syndrome; TRPM4, transient receptor‐potential
cation‐channel subfamily‐melastatine member‐4.
Among genetic forms, loss‐of‐function variants of the Nav1.5‐channel cause most of
familial cases of isolated progressive cardiac conduction disease.5 Also gain‐of‐function
or loss‐of function mutations in the TRPM4 gene may be commonly involved (10%–25%).5,
105 Conversely, loss‐of‐function mutations in genes encoding for L‐type Ca++ channel
(Cav1.3), Na+‐channel β‐subunit, or gap‐junction–forming connexins are described as
single case reports5, 105, 107 (Table 6). For hereditary SA node dysfunction, several
mutations in both HCN4 and SCN5A genes have been identified, although relative proportions
are still unknown5, 105 (Table 6).
Medications104 and autoimmune reactions7 represent the best‐recognized acquired factors
responsible for channelopathy‐induced bradyarrhythmias. Drugs include molecules directly
inhibiting Na+ and/or Ca++ channels, or the HCN4 channel106, 108 (Table 6). However,
with few exceptions (lithium and phenytoin), most involved drugs are antiarrhythmics
purposely used to reduce heart automaticity/dromotropism (Ca++‐channel blockers and
ivabradine) or widely known to exert negative effects on such parameters (class I
antiarrhythmics and amiodarone). Thus, in these cases, bradyarrhythmias are well‐expected
adverse events.
Autoimmune forms are related to autoantibodies specifically targeting either Ca++
or Na+ channels in the heart conduction tissue7, 14, 109 (Table 6). Currently, the
largest evidence is for anti‐Ro/SSA antibodies, which can induce conduction disturbances
and SA node dysfunction by directly inhibiting both L‐ and T‐type channels.109 Anti‐Ro/SSA
antibodies play a key role in the pathogenesis of autoimmune‐associated congenital
heart block, a conduction disturbance affecting fetal AV and SA nodes, in a structurally
normal heart, because of the transplacental passage of anti‐Ro/SSA antibodies.110
It develops in ≈2% to 5% of offspring from anti‐Ro/SSA–positive mothers and consists
of different degrees of AV block and sinus bradycardia, the third‐degree AV block
being associated with high mortality.110 Anti‐Ro/SSA antibodies, particularly anti‐Ro/SSA
52‐kD, can induce conduction defects in the fetal heart as a result of a direct cross‐reaction
with L‐ and T‐type Ca++‐channel α‐subunits (Cav1.2 and Cav1.3, and Cav3.1 and Cav3.2,
respectively), via inhibitory effects on ICaL and ICaT.7, 111 Moreover, the specific
autoantibody‐binding site in both channel types has been identified and is localized
on the extracellular loop of domain I pore‐forming segments S5 to S6.7, 112 After
a short‐term phase with purely functional and reversible effects, long‐term antibody
exposure can induce Ca++‐channel internalization, apoptosis, and cell death, eventually
resulting in inflammation, fibrosis, and calcification of the conduction system (irreversible
third‐degree AV block).7, 109 Also, the adult conduction system may be a target for
anti‐Ro/SSA antibodies, although more rarely and less severely.7, 113 Age‐related
differences in cardiomyocyte Ca++‐channel expression and Ca++ handling might account
for a purely electrophysiological effect with reversible AV blocks.7, 109 However,
preliminary retrospective data suggest that ≈20% of all cases of isolated third‐degree
AV block of unknown origin in adults may be anti‐Ro/SSA associated.113
In addition, recent evidence demonstrated that in a fraction of patients with idiopathic
AV blocks, a Nav1.5‐channel autoimmune channelopathy represents the likely mechanism
of bradyarrhythmias7 (Table 6). Korkmaz et al14 provided evidence that anti‐Nav1.5
autoantibodies inhibit channel function, leading to a significant decrease of INa
current by recognizing a site on the third extracellular pore region (S5–S6) of Nav1.5.
These findings, obtained by using patients’ sera, were confirmed and expanded in rats
immunized with the corresponding Nav1.5 pore‐peptide sequence. In this model, appearance
of high titers of anti‐Nav1.5 autoantibodies was associated with conduction disturbances,
in the absence of any functional heart alteration or signs of myocardial inflammation
or fibrosis at the histologic examination.14 Electrophysiological and biochemical
characterization of sera from Nav1.5‐immunized rats confirmed that anti‐Nav1.5 autoantibodies
can significantly reduce INa density, at least in part by downregulating Nav1.5 protein
expression.14
The “Multihit Theory”: Concept and Clinical Impact
A single channelopathy per se is not able in most cases to induce symptoms, and rarely
even the related clinical phenotype. This is well demonstrated for inherited forms,
particularly LQTS, BrS, and CPVT, where provocative tests can unmask latent genetic
defects.5 Consistent data are also available for drug‐induced, autoimmune, and inflammatory/fever‐induced
channelopathies. Indeed, only a small proportion of the large number of exposed subjects
develops drug‐induced LQTS/BrS and related arrhythmias, despite the resulting channel
dysfunction.6 Similarly, high temperature,60, 62 cytokines,8, 17 and anti–ion channel
autoantibodies7 induce cardiac channelopathies; however fever‐, inflammatory‐, and
autoimmune‐induced phenotypes and arrhythmias occur only in a fraction of the subjects
at risk. Such evidence strongly suggests that multiple often‐redundant ion channel
mechanisms are implicated in preserving normal AP genesis and conduction, thus rendering
the clinical phenotype unapparent despite subtle channel dysfunction. This view is
well represented by the “repolarization reserve” theory, first proposed by Roden to
explain drug‐induced LQTS/TdP risk,114 and now widely recognized. Therefore, >1 single
component needs to be impaired for ECG/clinical symptoms to emerge, and the number
of required “hits” will depend on the functional impact of each single offending factor.114
In a single patient, multiple QT‐prolonging factors are concomitantly required to
significantly disrupt repolarization. Besides specific inherited or acquired channelopathies,
other physiological (eg, age, sex, common polymorphisms, autonomic changes, and exercise)
or pathological conditions, either functional (electrolyte imbalances) or structural
(heart disease), may be superimposed in an intricate and often unpredictable scenario.
Accordingly, patients developing marked QTc prolongation and TdP concomitantly present
multiple risk factors.18 On 40 consecutive unselected patients with TdP, on average
>4 factors per subject were detectable (electrolyte imbalances, cardiac and extracardiac
diseases, drugs, anti‐Ro/SSA antibodies, and inflammation), with a high prevalence
of acquired channelopathies.25 Additionally, subclinical inherited channelopathies
and common polymorphisms are frequently found in patients developing TdP.18
Beyond LQTS, such a multihit theory could be more generally applied to all arrhythmogenic
phenotypes. BrS is often latent, emerging only in the presence of other concomitant
factors, including acquired channelopathies (ie, drugs or fever), autonomic changes,
electrolyte disturbances, or structural heart disease, cooperating to unmask genetic
predisposition and increase risk for fatal arrhythmia.66 By demonstrating that multiple
risk factors are frequently concomitant in patients with BrS, the group of Viskin
suggested to extend the concept of repolarization and/or conduction reserves to this
condition.70, 76 Similar considerations could also be applied to ERS, where acquired
factors can trigger phenotype development and arrhythmias,63, 66 as well as AF,115
and possibly bradyarrhythmias. Notably, Otway et al116 demonstrated that in a family
with a missense KCNQ1 variant leading to IKs gain of function, AF was only present
in those individuals who were both genotype positive and who had long‐standing hypertension
and atrial dilation, thus stressing the concept that interactions with a concomitant
structural heart disease are crucial to promote AF development in patients with inherited
(and acquired) channelopathies. Moreover, genetic differences in the conduction reserve
depend on cardiomyocyte L‐type Ca++‐channel expression and significantly affect the
risk of anti‐Ro/SSA–associated bradyarrhythmias.117 This is likely why only a fraction
of autoantibody‐positive subjects show conduction disturbances.7, 109 Altogether,
an integrated view of all components, inherited and acquired, as well as functional
and structural factors is crucial to estimate the actual arrhythmic risk in the single
patient with suspected or proven channelopathy. Indeed, avoidance of potentially harmful
drugs and lifestyle habits (ie, excessive alcohol intake, cocaine use, competitive/strenuous
exercise, and stressful environments), together with management of electrolyte imbalances
and fever (antipyretics), are already considered as class I recommendations, particularly
in LQTS, BrS, and CPVT.1, 5
However, because of the conventional wisdom that cardiac channelopathies are synonymous
of inherited cardiac channelopathies, genetic testing is presently the core diagnostic
approach to subjects with arrhythmogenic ECG phenotypes and/or life‐threatening arrhythmias/cardiac
arrest in a structurally normal heart. Beyond genetic forms, acquired channelopathies
should be equally considered and carefully addressed, particularly in subjects without
family history. Although recognition requires different levels of complexity, depending
on the factors involved, awareness is the key element. Drug involvement may be relatively
easily identifiable, provided that the updated lists of medications implicated in
the different phenotypes are regularly consulted. Similar considerations apply to
fever‐ and inflammatory‐induced channelopathies. Indeed, a febrile/inflammatory process
is often clinically evident, whereas subclinical inflammation may be revealed by routine
markers, particularly CRP, as a reflection of circulating cytokines.8
The diagnosis of an autoimmune channelopathy may be more difficult, because pathogenic
anti–ion channel autoantibodies can also be present in apparently healthy subjects,
regardless of any manifestation of AD.7 Thus, a concealed autoimmune channelopathy
may be implicated in cases of unexplained arrhythmias/SCD, and only specific autoantibody
testing can reveal an underlying autoimmune origin.7 In particular, patients who should
be tested include those presenting with rhythm disturbances/aborted cardiac arrest
in the absence of any recognized causative factor, despite intensive investigation
(including genetic testing), but also possibly several subjects with structural heart
disease or inherited channelopathies not responding to conventional treatments. These
subjects, particularly the last category, should be also tested for increased inflammation
markers because an inflammatory process, also transient and/or subclinical, may play
an important contributing role in triggering or enhancing electric instability in
patients already predisposed to arrhythmias. Indeed, acute inflammatory illnesses
are increasingly recognized as possible precipitant factors of malignant arrhythmias/electrical
storms in subjects with congenital LQTS,61, 118, 119, 120 and signs of subclinical
immune‐inflammatory activation have been demonstrated in patients with cardiomyopathies121,
122, 123 or inherited LQTS/CPVT who underwent left cardiac sympathetic denervation
for intractable arrhythmias.124 Unfortunately, although CRP and anti‐Ro/SSA antibody
testing is largely available in the clinical practice (Western blot technique is recommended
for detecting arrhythmogenic anti‐Ro/SSA subtypes),7, 28, 37 other specific anti–ion
channel autoantibodies are currently tested in only few reference centers worldwide.14,
30, 41, 65
Perspectives and Conclusions
Among acquired channelopathies, autoimmune and inflammatory channelopathies have long
been neglected but now represent an increasingly recognized mechanism for cardiac arrhythmias.
These mechanisms may have a causal role in arrhythmias and SCD in apparently healthy
individuals,7, 8, 14, 45, 113, 125, 126 as well as being actively involved in enhancing
electrical instability in genetically predisposed patients.17, 78, 79, 80, 124 The
identification of such mechanisms as a causal factor for arrhythmias might open novel
targeted therapeutic avenues for the immune‐inflammatory system, including anti‐inflammatory
and immunomodulating drugs, plasmapheresis, and immunoadsorption, which may effectively
reduce arrhythmic risk.7, 8 This view is supported by some studies in patients with
autoimmune‐associated congenital heart block127 or inflammation‐driven AF forms128,
129 and in case reports showing the reversal effects of immunosuppressive therapy
in anti‐Ro/SSA–associated LQTS and AV block in adults.125, 126, 130 In addition, the
evidence that autoantibodies induce channelopathies by directly cross‐reacting with
specific amino acid sequences on ion channel proteins suggests an innovative therapeutic
approach based on the use of short decoy peptides (peptide‐based therapy) distracting
the pathogenic antibodies from channel binding sites.7 Experimental studies using
sera from anti‐Ro/SSA–positive subjects with TdP28 or affinity‐purified anti–L–type
Ca++‐channel autoantibodies from patients with dilated cardiomyopathy41, 43 may help
demonstrate that competing peptides can effectively counteract autoantibody‐channel
interaction, and may prevent abnormal electrophysiological effects and VA.
Besides inducing arrhythmogenic channelopathies, anti–ion channel antibodies obtained
via peptide vaccination might in the future be used as antiarrhythmic therapy in some
patients with inherited channelopathies. For example, Kv7.1‐channel vaccination has
been proposed as a therapeutic option in patients with congenital LQTS resistant to
conventional treatments.15, 65 Although speculative, the evidence that hERG‐channel
peptide immunization can generate antibodies inhibiting IKr and slowing of ventricular
repolarization in guinea pigs16 suggests a potential therapeutic role using hERG‐channel
peptide vaccination in selected patients with congenital SQTS.
In conclusion, although molecular targets and mechanisms responsible for arrhythmogenic
cardiac channelopathies may be different, the final common outcome is the development
of an ion channel dysfunction leading to an increased vulnerability to cardiac arrhythmias
(Figure 2). Because the concomitant presence of multiple, synergistically cooperating
determinants is frequent in the clinical setting, an integrated approach of all potential
components in inherited and acquired cardiac channelopathies, including autoimmune
and inflammatory/fever‐induced forms, may be crucial in clinical practice to comprehensively
assess and manage the actual arrhythmic risk in the individual patient.
Figure 2
Cardiac channelopathies and arrhythmias: from the channel to the patient. In a structurally
normal heart, both inherited (genetic defects) and acquired (drugs, autoantibodies,
and inflammation/fever) factors can induce cardiac ion channel dysfunction, responsible
for electrophysiological changes leading to specific electrocardiographic phenotypes
and cardiac arrhythmias.
In fact, although the clinical impact of autoimmune and inflammatory/fever‐induced
channelopathies on the arrhythmic risk in the general population is not clearly defined,
because large prevalence studies are currently lacking, present evidence already suggests
that the cardiologist should consider an “internist” holistic view of the patient,
and what is currently considered the narrow domain of the cardiac electrophysiologist
now should become the interest of the well‐informed general practitioner.
Sources of Funding
This work has received funding from “Fondo Aree Sottoutilizzate‐Salute ToRSADE project”
(FAS‐Salute 2014, Regione Toscana) and a Merit Review grant I01 BX002137 from Biomedical
Laboratory Research and Development Service of Veterans Affairs Office of Research
and Development (Boutjdir).
Disclosures
None.