Journal of the American College of Cardiology Vol. 47, No.

1, 2006
© 2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2005.08.059

CARDIOVASCULAR GENOMIC MEDICINE

Genomics and Cardiac Arrhythmias

Robert Roberts, MD, FACC
Ottawa, Ontario, Canada
Sudden cardiac death in patients younger than 35 years of age is primarily due to genetic
causes. Familial hypertrophic cardiomyopathy accounting for 30% to 40% is associated with
structural heart disease while the Brugada syndrome and the long QT syndrome (LQTS) are
associated with normal cardiac function. This is a review of the genetics of supraventricular
and ventricular arrhythmias. Atrial fibrillation is mapped to nine chromosomal loci and four
genes are identified. Adenosine monophosphate-activated protein kinase is one gene
responsible for Wolff-Parkinson-White syndrome. The LQTS and the Brugada syndromes
are due to defects primarily in cardiac sodium and potassium ion channels. The role of single
nucleotide polymorphisms in predisposing to arrhythmias in acquired disorders such as
hypertrophy is discussed. (J Am Coll Cardiol 2006;47:9 –21) © 2006 by the American
College of Cardiology Foundation

The past decade has been golden for cardiovascular diseases
with the elucidation of several genes responsible for familial
cardiomyopathies and the ion channelopathies. However,
these diseases, referred to as single gene disorders, were
amenable to chromosomal mapping of the gene locus
through conventional genetic linkage analysis. In these
disorders, a single gene predominates in the expression of
the phenotype. However, even with single gene disorders,
there are modifier genes, which have a significant influence
on the phenotype but would not be detected by this
conventional technique. There is suggestive evidence that
arrhythmias such as atrial fibrillation occurring in associa-
tion with acquired structural heart disease are more likely in
those individuals with genetic predisposition (1,2). This is
particularly pertinent in polygenic diseases such as coronary
artery disease and hypertension (3,4). Locating and identi-
fying modifier genes and genes that predispose but do not
per se induce the phenotype has not been feasible due to
lack of appropriate statistical models and high throughput
genotyping technology. While both of these problems are
still with us, there are currently methods making it possible
and practical to pursue such research goals.
The sequencing of the human genome has brought with
it a wealth of information as well as enabling the develop-
ment of high throughput technology. It is now recognized
that 99.9% of the three billion bases that comprise the
human genome are identical (5,6). Thus, about three
million bases account for all of the differences between
human beings including one’s resistance or vulnerability to
disease. The current and future challenge is to identify these
differences referred to as single nucleotide polymorphisms
(SNPs). Currently, it appears there are over 15 million
SNPs circulating in the population from which three mil-
lion can be selected to be passed on by each parent to their
From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Manuscript received July 20, 2005; revised manuscript received August 4, 2005,
accepted August 17, 2005.
offspring. A major project referred to as the HapMap
project is ongoing to map the chromosomal location of
these SNPs and generate haplotypes involving multiple
SNPs that tend to be inherited as blocks or units (7). The
effect of SNPs on a particular phenotype may be through
haplotypes containing several SNPs rather than a single
SNP. To identify these SNPs or haplotypes on a genome-
wide basis for a particular phenotype such as atrial fibrilla-
tion would require hundreds of thousands of DNA markers,
which, until recently, would be prohibited (6). Chips are
now available with hundreds of thousands of SNPs such as
the Affymetrix 500,000 chip (Affymetrix, Santa Clara,
California) to perform these studies. Secondly, such high-
density DNA markers make it possible to utilize mathemat-
ical models to identify associations with polymorphisms that
have minimal effect on the phenotype (5,6,8). It is now
possible to genotype 100 DNA samples for 500,000 geno-
types over a period of a few hours. This has ushered in a new
era for detecting genetic variants that affect human disease.
GENOMIC IMPLICATIONS FOR DIAGNOSIS AND
TREATMENT OF SUDDEN CARDIAC DEATH (SCD)
Sudden cardiac death remains a worldwide scourge. There
are considerable data to indicate the proximate cause of
SCD is electrical due to cardiac conduction defects or
dysrhythmias. In the U.S. over 400,000 and in Canada over
50,000 die annually from SCD (9). It is of note that this
number has not changed for the past three decades. Thus,
treatment for SCD has not been as progressive as in other
forms of cardiac disease, indeed one may say it has been
regressive. A major landmark study evaluating drugs in the
treatment of arrhythmias was the international clinical trial
referred to as Cardiac Arrhythmia Suppression Trial
(CAST) (10). The major and unexpected finding was that
most of the drugs used in the trial were shown to be
pro-arrhythmic. Quinidine, a drug used for decades in the
10 Roberts
Genomics and Cardiac Arrhythmias
Abbreviations and Acronyms
AMPK⫽ adenosine monophosphate-activated protein
kinase
AP ⫽ action potential
HCM ⫽ hypertrophic cardiomyopathy
ICD ⫽ implantable cardioverter-defibrillator
LQTS ⫽ long QT syndrome
SCD ⫽ sudden cardiac death
SNP ⫽ single nucleotide polymorphism
SQTS ⫽ short QT syndrome
WPW ⫽ Wolff-Parkinson-White syndrome
treatment of supraventricular and ventricular arrhythmias
was shown to prolong the QT interval and induce ventric-
ular arrhythmias and SCD. Therapy had to be developed
empirically without knowing the molecular basis for the
disease or the molecular mechanism of the drug. Current
knowledge of ion channels facilitates the development of
drugs without known adverse effects such as prolongation of
the QT. It is expected that genetic defects, many of which
involve ion channels, will help to identify molecular mech-
anisms for arrhythmias, which are also applicable to ar-
rhythmias caused by acquired disease. There is some en-
couragement with the overlap between the mechanism
responsible for ventricular tachycardia of familial long QT
syndrome (LQTS) and that induced by quinidine in ac-
quired disorders.
Young individuals who die with monogenic disorders
such as Brugada syndrome or prolonged QT syndrome are
usually asymptomatic, and SCD is their first and often last
symptom. In the future, when appropriate therapy becomes
available to prevent SCD in the asymptomatic individuals,
genetic screening will be a prerequisite (e.g., Brugada
syndrome, LQTS, and so on). Gene testing on the basis of
family history or an incidental electrocardiogram (ECG)
finding (e.g., insurance) followed by appropriate therapy is
likely to be a future routine to prevent SCD. Most of SCD
over the age of 35 years occurs in association with acquired
structural heart disease and symptoms. There is, however,
the concern of who is vulnerable for SCD. For example, in
heart failure 50% die of SCD due to arrhythmias (11). The
only effective treatment is an indwelling defibrillator. The
dilemma is identifying which half is vulnerable. One hope is
to detect SNPs that predispose to SCD. Identifying molec-
ular defects responsible for arrhythmias should lead to novel
therapies specifically designed to target the abnormality.
Identification of the defect in the cholesterol receptor of
familial hypercholesterolemia leads to the development of
drugs (statins) to inhibit cholesterol synthesis. These drugs
are now the mainstay of treatment to prevent coronary
artery disease in the general population. Pharmacogenetics
and pharmacogenomics will assist in selecting the drug and
determining the dose on an individual basis to minimize
adverse side effects. Determining who is at risk for arrhyth-
mias and SCD is a problem common to those with
JACC Vol. 47, No. 1, 2006
January 3, 2006:9–21
structural or electrical cardiac disease. The person without
structural heart disease (Brugada syndrome) is perhaps at a
greater disadvantage because they are more likely to be
younger and less likely to have a reason to visit the
physician.
THE FREQUENCY AND PREVALENCE
OF GENETIC-INDUCED ARRHYTHMIAS
In considering the role of genetics and arrhythmias, one
must pause as to the frequency and prevalence of the
genetic-induced arrhythmias. Throughout the world, SCD
occurring in the young adult (⬍35 years) whether associated
with structural or nonstructural heart disease is predomi-
nantly due to genetic defects. Familial hypertrophic cardio-
myopathy (HCM) with a prevalence of 1 in 500 is the most
common cause of SCD in the young (12). While there are
no population studies on the prevalence of the genotype,
estimates based on the phenotype, which usually underes-
timates the genotype, show it is very common for a genetic
disorder. It is estimated over 12 million individuals in the
world carry the genetic defect for HCM. There are over
600,000 individuals with this genetic defect in the U.S. and
60,000 in Canada. Brugada syndrome, another familial
cause of SCD in the young, is the most common cause of
SCD occurring in individuals without structural heart dis-
ease (13). Wolff-Parkinson-White syndrome (WPW) is the
second most common cause of supraventricular arrhythmias
in the Western world and the most common cause in China
(14). The role of WPW in SCD remains controversial. In
those studies in which the cardiac conduction system was
evaluated, WPW was a major cause of SCD, particularly in
infants (15). Wolff-Parkinson-White syndrome, while al-
ways a genetic disease, appears to be mostly sporadic rather
than familial. In a recent study, 30% of patients with atrial
fibrillation with or without structural heart disease had a
family history of atrial fibrillation (16). Offspring with even
a single parent having atrial fibrillation will have 85%
increased risk of developing atrial fibrillation (16). For
single gene disorders, many genes with their corresponding
mutations have been identified, and the appropriate tech-
nology could be assembled soon to screen populations at risk
of having these genetic defects.
THE ROLE OF GENETICS IN ACQUIRED ARRHYTHMIAS
In the middle-aged and elderly population, which accounts
for most of SCD, the cause is almost always associated with
structural heart disease predominantly due to coronary
artery disease. What is the role of genetic defects in these
individuals? While no gene or polymorphism has yet been
definitely identified to induce arrhythmias, there is increas-
ing evidence that genetic predisposition contributes signif-
icantly to acquired arrhythmias (17). For example, a recent
finding shows that atrial fibrillation occurring with struc-
tural and nonstructural heart disease is associated with a
JACC Vol. 47, No. 1, 2006
January 3, 2006:9–21
family history of atrial fibrillation in 30% of patients (16).
Much of susceptibility to acquired disease is thought to be
encoded primarily by SNPs that span the human genome.
Even in single gene disorders, there are modifying genes
(SNPs), which modulate the phenotype resulting from the
interaction of the environment with the genotype. A third
group of genes modulating arrhythmias in acquired and
inherited diseases, particularly coronary artery disease or
heart failure, are those whose expression is reprogrammed
by the underlying disease. An excellent and well-
characterized example is cardiac compensatory hypertrophy
in response to pressure overload as occurs in hypertension,
valvular disease, or heart failure. In pathological hypertro-
phy as opposed to physiological hypertrophy, expression of
a host of genes is up-regulated as part of the so-called fetal
program (18). The extent of hypertrophy may, in part,
depend on the presence or absence of certain alleles. For
example, regardless of the cause, if the patient is homozy-
gous for the DD allele of the angiotensin-converting en-
zyme gene as apposed to the I-form, hypertrophy will be
more extensive and the propensity for SCD greatly in-
creased (19). Hypertrophy that deteriorates into dilated
cardiomyopathy induces the expression of other genes,
which could alter the predisposition to atrial or ventricular
arrhythmias and SCD. All of the association studies sug-
gesting genetic predisposition remain suspect because of the
small sample size (6), but the technology is now available to
pursue studies with adequate sample size. The availability of
genome-wide scans with 500,000 SNPs properly selected is
likely to add a new dimension to our search for genetic
predisposition and modifier genes.
GENETIC SCREENING FOR PREDICTION
AND PREVENTION OF ARRYTHMIAS
Genes themselves do not engage in the work of the cell, but
rather their end product, the protein, performs the function
of the organism. In single gene disorders of adults, the most
common mutation is a missense. This is a genetic defect in
which a single base has been substituted for another
resulting in the encoding of a different amino acid, which, if
occurring in an important domain of the protein, will be
associated with a gain- or loss-of-function. Other less
common defects would be a loss or gain of a base resulting
in a protein with many amino acids altered or the coding
may be changed to a start or stop codon resulting in a
truncated protein. Genetic defects occurring in non-protein
coding regions will be manifested primarily as increased or
decreased expression of the protein. Thus, the major func-
tional change in the protein is loss- or gain-of-function due
to an alteration in the amino acid composition or the
expression of the protein. While genetic screening is pivotal
in the prevention of genetic disease, it unfortunately is not
the only variable that must be considered. Genetic screening
determines the presence or absence of the genetic defect and
thus whether there is a risk of developing the disease.
Roberts 11
Genomics and Cardiac Arrhythmias
Screening for polymorphisms in polygenic disorders deter-
mines whether there is a risk of increased susceptibility for
arrhythmias. Other critical features must be considered as
we move into the genetic revolution and apply this infor-
mation to the care of patients. Despite having the genotype
at birth, several factors modulate whether the phenotype
will ever develop and to what extent. First, is the feature of
penetrance which the risk of developing the phenotype in an
individual with the genetic defect. In the case of single gene
disorders, those that are autosomal dominant have a high
penetrance of probably 70% to 80% but seldom complete.
Thus, a percentage of individuals despite having the defec-
tive gene do not develop the disease. The other modifier is
referred to as expressivity defined as the variability in
phenotypic manifestations that occur across a population
despite being due to the same genetic defect. The onset of
the phenotype is often age-dependent. The severity of the
phenotype and whether it develops are also influenced by
environmental factors such as exercise, temperature, gender,
and other factors. Nevertheless, solutions to these problems
will be facilitated with routine genetic screening and in-
creased experience. Present knowledge clearly indicates that
a multidisciplinary approach is required in the future to
identify these genetic abnormalities and utilize them for
treatment and prevention. It does require careful clinical
characterization, genetic expertise, functional analysis, and
genetic counseling along with drug discovery to significantly
impact this worldwide scourge.
GENETICS OF SUPRAVENTICULAR ARRHYTHMIAS
Atrial fibrillation. Atrial fibrillation is the most common
sustained cardiac arrhythmia. It occurs in about 6% of the
population over the age of 60 years. It is estimated there are
over 3 million people with persistent atrial fibrillation in the
U.S. (20), which will increase to 5.6 million by 2050 (21).
At age 40 years and over, the chance of developing atrial
fibrillation in men and women is about 25% (22). It is
associated with significant morbidity and mortality, ac-
counting for over one-third of all strokes over the age of 60
years (23). In a recent Framingham Heart study of 2,243
participants, 681 had at least one parent with atrial fibril-
lation (16). This indicates 30% of all patients with atrial
fibrillation, with or without structural heart disease, have a
family history of the disease (16). The relative risk of atrial
fibrillation was increased 85% in individuals with at least
one parent with a history of atrial fibrillation (16). We
identified the first locus for familial atrial fibrillation on
chromosome 10 (10q22), confirming the inheritance of this
disease (24). Currently, seven chromosomal loci have been
mapped and four of the genes identified. The genetic
features of each of these loci are summarized in Table 1, and
a brief discussion will follow of each of the genes.
KCNQ1 gene. KCNQ1, the first gene, was identified (25)
in a four-generation Chinese family showing autosomal
dominant inheritance. The loci was mapped to chromosome
12 Roberts
Genomics and Cardiac Arrhythmias
Table 1. Genetic Loci Responsible for Atrial Fibrillation
Mode of
Locus Gene Inheritance
11p15.5 KCNQ1 AD
21q22 KCNE2 AD
17q KCNJ2 AD
7q35–36 KCNH2 AD
5p13 Unknown Recessive
6q14–16 Unknown AD
10q22 Unknown AD
AAP ⫽ atrial action potential duration; AD ⫽ autosomal dominant; ARP ⫽ atrial effective refractory period.
11p15.5 and the gene, KCNQ1, encodes for the alpha
subunit of a cardiac potassium channel. The mutation
consisted of substitution of adenine to guanine at nucleotide
418 resulting in an amino acid substitution of serine for
glycine at residue 140 (S140g). Penetrance was close to
100%. Expression of the wild type and mutant KCNQ1
gene in COS cells showed increased potassium current
density. Thus, the mutation induced a gain-of-function,
which shortens the atrial action potential (AP) duration and
the effective atrial refractory period. Several investigators
with multiple families had shown KCNQ1 is not responsi-
ble for atrial fibrillation in their families (26), suggesting this
is an uncommon cause for atrial fibrillation.
KCNE2 gene. A second locus was identified by the same
Chinese investigators (27) on 21q22 encoding for another
potassium channel subunit (KCNE2). The mutation was
shown to involve a C to T transition at nucleotide 79 of the
gene for KCNE2. This resulted in an arginine to cysteine at
residue 27 (r27C), which is present in all affected individuals
but not in healthy individuals. Mode of transmission was
again, autosomal dominant. Functional studies, again,
showed that the mutant shortened the atrial AP duration
and the atrial effective refractory period. The penetrance
appeared to be incomplete although difficult to assess from
the limited number of studies performed.
KCNJ2 gene. A third gene was identified in 30 unrelated
Chinese kindred of atrial fibrillation showing a missense
mutation in the potassium channel KCNJ2 (28). KCNJ2
encodes for the Kir 2.1 channel, which mediates potassium
current in the heart. It is an inward rectifier, which induces
early repolarization. The gene exhibited a missense muta-
tion with G to A at nucleotide 277 corresponding to a valine
to isoleucine at residue 93 (V93I) of the protein. Functional
analysis again showed that this mutant gene shortens the
atrial AP duration and the atrial refractory period. Overex-
pression of the wild type Kir 2.1 in the mouse induced atrial
fibrillation (29). Acquired atrial fibrillation in humans is
associated with increased expression of the Kir 2.1 channel
(30 –33). The investigators also analyzed KCNJ2 in 154
other patients with lone atrial fibrillation, but no mutation
was identified (28).
KCNH2 gene. Recently, Hong et al. (34) identified a
family with short QT syndrome (SQTS) in whom three
members presented with atrial fibrillation. The proband of
17 years of age presented with paroxysmal atrial fibrillation.
JACC Vol. 47, No. 1, 2006
January 3, 2006:9–21
Effect on
Mutation Function Physiological Effect
S140G Gain of function 2 AAP 2 ARP
R27C Gain of function 2 AAD 2 ARP
V931 Gain of function 2 AAD 2 ARP
N588K Gain of function 2 AAP 2 ARP
Unknown Unknown Unknown
Unknown Unknown Unknown
Unknown Unknown Unknown
KCNH2 gene exhibited a missense mutation at nucleotide
17645 with C going to G resulting in the substitution of
asparagine for lysine at residue 588 (N588K). All affected
members upon electrophysiological testing showed a short-
ening of the atrial and ventricular refractory periods with
inducibility of atrial and ventricular fibrillation. The muta-
tion confers a gain-of-function with a shortening of the
atrial AP duration and the effective atrial refractory period.
Genetic defects provide insight into the mechanism for
atrial fibrillation. There are several consistent features of
the genetics of atrial fibrillation:
1) Genes identified all encode for subunits of potassium
channels
2) All mutations confer a gain-of-function
3) All of the mutations shorten the atrial AP duration and
the atrial effective refractory period
Atrial fibrillation is thus a channelopathy whereby the
genetic defects provide an ideal substrate for re-entry
arrhythmias. The consistency of the mechanism whereby
genetic defects induce atrial fibrillation should provide
specific targets for the development of novel drug therapy.
POLYMORPHISMS THAT
PREDISPOSE TO ATRIAL FIBRILLATION IN
INDIVIDUALS WITH STRUCTURAL HEART DISEASE
Atrial fibrillation occurs mostly in association with acquired
diseases such as coronary heart disease, value disease, or
heart failure. In a recent study (1) involving 250 patients
with structural heart disease and atrial fibrillation, 250
controls expression of polymorphisms N235T, G-6A,
G-217A of the angiotensin-converting enzyme gene were
significantly increased in patients with atrial fibrillation over
that of controls with a p value of 0.01, 0.005, and 0.002,
respectively. The odds ratio for atrial fibrillation was 2.5
with M235/M235 ⫹ M235/T235 genotype, 3.3 for the
G6/G6 genotype, and 2.0 for the G217/G217 genotype.
Similar associations have been made with polymorphisms in
the connexin 40 gene. This gene encodes a cardiac gap
junction protein, which mediates electrocoupling of cardio-
myocytes (2). The polymorphisms in the promoter region
upstream of the gene, which are ⫺44A and ⫺44AA
genotypes, were more frequent in subjects with atrial fibril-
JACC Vol. 47, No. 1, 2006
January 3, 2006:9–21
lation exhibiting a risk ratio of 5.3 and 6.2, respectively, for
atrial fibrillation. In another study (35), 108 patients with
acquired atrial fibrillation compared to controls showed the
K38G alleles of connexin 40 exhibited an odds risk ratio for
atrial fibrillation of 1.8 in patients with more than one
K38G allele. These studies suggest that polymorphisms
predispose to atrial fibrillation when occurring in association
with these diseases. It is important to recognize that these
studies are case control association studies, and it is inade-
quate to make definitive conclusions. The sample size is too
few and would require confirmation of the larger sample size
and also better matching of controls with affected individ-
uals. However, the availability recently of genome-wide
scans with hundreds of thousands of SNPs will, in the
future, make it possible to perform genomic studies to
identify SNPs that predispose to diseases such as atrial
fibrillation. This is expected to be a major onslaught of
genomic technology in the next few years.
Paroxysmal supraventricular tachycardia. Wolff-Parkinson-
White syndrome is the most common form of paroxysmal
supraventricular tachycardia in China and the second most
common cause in the Western world (14,36). The incidence
of WPW is about 1 in 3,000 of the population. This
syndrome, named after the individuals described in 1930,
has remained as a paradigm of a model for re-entry
arrhythmias. In this disease, there is an accessory bundle of
muscle tissue, which connects the atrium to the ventricle
bypassing the atrioventricular node. Conduction through
the accessory bundle is usually retrograde but under unusual
circumstances may be antegrade at very rapid rates of 150
beats/min. Rapid heart rates, whether retrograde or ante-
grade, if sustained lead to heart failure or even ventricular
tachycardia and SCD. The most common form of tachy-
cardia associated with WPW is paroxysmal supraventricular
tachycardia with rates of 120 to 160 beats/min. The role of
WPW in SCD is difficult to assess. Autopsies performed to
assess cause of death do not examine the specialized con-
duction system of the heart and thus would not detect
WPW. In studies in which the conduction system was
evaluated, WPW was found to account for 33% of patients
who died suddenly without structural heart disease (15).
The prevalence of familial WPW appears to be low with
most due to a sporadic genetic defect; WPW is a genetic
disease in that the formation of an accessory conducting
bundle or lack of remodeling of an existing bundle requires
genetic regulation. It is perhaps analogous to cancer, which
is an obligatory genetic disease, but the familial form
appears less common.
In 2001 we identified a family with WPW and showed
(37) the gene responsible for the disease in this family
encodes for the gamma 2 subunit of the enzyme adenosine
monophosphate-activated protein kinase (AMPK). The
gene is referred to as PRKAG2 located on chromosome
7q36 and is inherited in an autosomal dominant pattern;
AMPK consists of three subunits, alpha, beta, and gamma,
with each subunit encoded by a distinct gene. The gamma
Roberts 13
Genomics and Cardiac Arrhythmias
subunit has a binding site for AMP, which is essential for
enzymatic activity. The mutation consists of a substitution
of glutamine for arginine at residue 302. Six mutations have
since been described in several families all of which are
missense mutations except for one, which is an insertion
(38). The penetrance based on the few families so far
studied is in the range of 70% to 80%. The phenotype
consists of pre-excitation on the ECG, varying degrees of
conduction defects, frequently cardiac hypertrophy, and
excessive glycogen storage in the myocytes without sarco-
mere or myocyte disarray (39). The most common arrhyth-
mia associated with WPW is that of paroxysmal supraven-
tricular tachycardia with a narrow QRS. In the remaining
20%, the arrhythmia is generally atrial fibrillation. In this
syndrome, however, the incidence of atrial fibrillation is
much higher in the range of 40% to 50%; AMPK is a sensor
of the body’s ATP level and is activated by an increase in the
ratio of AMP to ATP (40,41). The availability of ATP is
increased by AMPK through increasing glucose absorption,
inhibiting glycogen synthesis, increasing fatty acid oxida-
tion, and decreasing fatty acid synthesis. Transgenic mice
expressing either the R302q mutation (39) or the N4881
mutation (42) exhibit a typical phenotype as observed in
humans for this disease. The mechanism whereby AMPK
leads to accessory pathways or alters conduction remains to
be determined. In one study, it has been shown that R302Q
mutation inhibits the cardiac sodium inward current (41).
Utilizing these transgenic models, studies are now being
performed to determine alternate forms of therapy. It also
serves as a model to elucidate AMPK’s role in the develop-
ment of the heart and, in particular, that of the specialized
cardiac conduction system. The accepted form of treatment
currently in patients with familial WPW is ablation of the
accessory bundle. Therapy to prevent the excessive glycogen
storage may require replacement of AMPK enzyme.
GENETICS OF VENTRICULAR ARRHYTHMIAS
Brugada syndrome. There remains a large group of indi-
viduals who develop idiopathic ventricular fibrillation unas-
sociated with any structural heart disease. In 1995, a disease
now referred to as Brugada syndrome (43) was described,
which is associated with SCD at a very young age and is
responsible for a significant proportion of sudden infant
death syndrome. Brugada syndrome is characterized by a
history of sudden death and a typical ECG pattern of
ST-segment elevation in leads V1 to V3 (Fig. 1) (13). It is
claimed to be responsible for up to 12% of all sudden deaths
and approximately 20% of deaths occurring in patients with
structurally normal hearts. In the Western world, the
prevalence of this disease appears to be in the order of 1 in
5,000 individuals. In Southeast Asia, the disease is more
prevalent being a leading cause of death in males under the
age of 40, second only to car accidents (13). This disease
exhibits an autosomal dominant pattern of inheritance
indicating it affects men and women equally, and 50% of the
14 Roberts
Genomics and Cardiac Arrhythmias
Figure 1. Variation in the precordial lead ST and T waves in a patient with Brugada syndrome. Reprinted with permission from Fuster V, Alexander RW,
O’Rourke RA. Hurst’s The Heart. 11th edition. McGraw-Hill Companies, 2004.
offspring will inherit the gene and be at risk of developing
arrhythmias and SCD. This also means only one copy of the
gene is defective, and it acts as a dominant positive or
negative. All of the mutations identified have been in a
subunit of the sodium cardiac channel (SCN5A).
The subunit referred to as SCN5A has a genomic
structure (44) consisting of 28 exons spanning approxi-
mately 80 kb on chromosome 3p21 with a dinucleotide
repeat polymorphism in entron 16. The gene encodes for a
protein with 2,016 amino acids. Sodium channels, like most
ion channels, are part of a complex. The pore forming alpha
subunit is encoded by SCN5A, and up to three beta
subunits have been described, as well as other attachments
to the cytoskeleton such as caveolas (45). The mutations
identified responsible for the Brugada syndrome have been
primarily missense mutations. More than 60 mutations have
been described in the SCN5A of which all have been
localized to the protein coding sequences. Screening for
these mutations show they account for only about 25% of
patients with Brugada syndrome. This indicates there may
be other mutations in the SCN5A gene and most likely
mutations in multiple other genes. Most of the genes
responsible for the ion channels of the cardiac AP have been
cloned and are available as good candidates to screen for
these mutations. The mutations identified in SCN5A have
been associated with a loss of current either by creating a
truncated protein or by increasing sodium channel inactiva-
tion (13). One of the mutations, an insertion, occurred in
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January 3, 2006:9–21
the splicing donor site of intron 7. Recently, the first
intronic mutation in SCN5A was described (46), which
involved a four base pair insertion in exon 27. This led to a
truncated protein and a non-functional channel. Brugada
syndrome and LQTS can both be caused by defects in the
SCN5A but are opposite in function, namely, the former is
due to loss of function leading to an accelerated inactivation
of the sodium channel resulting in more rapid depolariza-
tion (46). Patients with Brugada syndrome on becoming
febrile are more likely to develop arrhythmias and SCD
(13). It is evident there are many more mutations and other
genes yet to be discovered considering that over 75% of
cases are not due to known mutations. A second locus has
been mapped to chromosome 3 (13) indicating at least
another gene; however, that gene has not been identified.
Genetic screening, currently not available, will be essential
for the management of this disease because most of these
people do not have symptoms. Even when someone is
identified to have a history of this disease, it will be
necessary to determine which 50% of the offspring have the
mutation and are vulnerable to arrhythmias and SCD.
Genetic screening is necessary for appropriate genetic coun-
seling as well as to implement preventive therapy when it
becomes available. In the meantime, it is important to
recognize that most drugs are not effective in this syndrome.
An implantable cardioverter-defibrillator (ICD) is essen-
tially the only recommended form of therapy.
JACC Vol. 47, No. 1, 2006
January 3, 2006:9–21
Table 2. Genetic Loci Responsible for Long QT Syndrome
Arrhythmia Chromosome
Autosomal Dominant Loci
LQT1 Ilp15
LQT2 7q35
LQT3 3p21
LQT4 4q25
LQT5 21q22
LQT6 21q22
LQT7 17
Recessive (and Deafness)
LQT Ilp15
LQT 21q22
LQTS
Clinical features. The congenital LQTS is an inherited
disease characterized by prolongation of ventricular repolar-
ization, which is manifested by prolongation of the QT
interval on the ECG (47). It is associated with a high risk of
sudden death from ventricular arrhythmias. There are two
forms of the disease, one autosomal dominant and the other
recessive (48). The autosomal dominant form is far more
common, and the rare recessive form is associated with
deafness. Clinically, the syndrome is characterized by syn-
copal episodes, malignant ventricular tachycardia, and fibril-
lation. The majority of patients with LQTS are asympto-
matic and are either discovered incidentally based on ECG,
family history, or having survived an episode of syncope or
severe ventricular arrhythmias. The prognosis of untreated
patients is considered to be quite poor. It is claimed that
about one-fifth of untreated patients presenting with syn-
cope die within 1 year and 50% within 10 years (13). Long
QT syndrome can also be acquired due to a long list of
drugs, primarily antiarrhythmics, antidepressants, and phe-
nothiazides. In addition, electrolyte imbalance such as
hypokalemia, hypomagnesemia, and hypocalcemia, can also
cause LQTS. These drugs and electrolyte abnormalities play
a major triggering role in ventricular arrhythmias and SCD
in patients with the inherited LQTS.
Pathogenesis of familial LQTS. Long QT syndrome is
now known to be due to nine different genes (Table 2). Of the
nine genes identified, seven encode potassium channel sub-
units, one, a sodium channel, and, most recently, a mutation
encoding for ankyrin B, a scaffolding protein. The latter is the
only non-channel disease gene thus far described (49).
In LQTS, prolongation of the AP (Fig. 2) may be due to
an increase in the phase of depolarization or a decrease in
the current that induces repolarization. The molecular
defect is determined by the specific genotype, but the final
common pathway is prolongation of the AP and decreased
repolarization reserve (47). This results in diminished ability
of the ventricular myocyte to respond to stress such as
hypoglycemia, hypomagnesemia, and drugs that prolonged
the AP. The sodium and potassium channels share opposite
affects on the AP duration. The sodium channel depolarizes
Roberts 15
Genomics and Cardiac Arrhythmias
Gene Frequency
KCNQI ⫺50%
KCNH2 30%–40%
SCN5A 5%–10%
ANK2 Rare
KCNEI Rare
KCNE2 Rare
KCNJ2 Rare
KCNQI Rare
KCNQ2 Rare
the cell with most of the activity occurring during the
upstroke of the AP. An increased amount of current active
during the plateau phase would prolong depolarization and
lengthen the AP. Potassium channels when active tend to
restore the internal negativity of the cell and shorten the
AP. If potassium currents predominate during the plateau,
repolarization will occur shortening the AP as opposed to
sodium currents if they predominate during plateau, it
prolongs the AP. In LQTS due to defects in a potassium
channel, there is a loss-of-function, whereas in LQTS due
to defects in sodium channel gene, there is a gain-of-
function. Both are due to autosomal dominant patterns of
inheritance indicating only one copy of the mutated gene is
necessary to produce the clinical syndrome.
The pathogenesis of LQTS due to defects in the ion
channels may be summarized as follows: mutations in the
potassium channel lead to inadequate opening and decreased
outward current; mutations in the sodium channels lead to
inadequate closing of the channels and excessive sodium
inward current. This results in an imbalance with an inade-
quate maintenance of the electrical gradient reflected in pro-
longation of the AP reflected by long QT interval on the
ECG.
Genotype-phenotype correlations. The role of genetics
with respect to prognosis and therapy for LQTS remains to
be defined. Studies relating a single mutation to survival or
to clinical events as well as therapy have not shown a
clear-cut stratification (50). This may, in part, relate to lack
of adequate sample size and the genetic background on
which that particular mutation is interacting. Attempts,
however, to relate a particular gene to survival and how it
interacts with gender and the duration of the QT interval
have been performed (48). In the study by Priori et al. (48),
investigators assess the risk of the first cardiac event before
the age of 40 years and before initiating therapy in 580
patients. The study involved 355 patients with a mutation in
the KCNQ1 gene, 176 patients with a mutation in the
KCNH2 gene, and 49 individuals with a mutation in the
SCN5A gene. These represent the most common causes of
the familial LQTS. Results, as illustrated in Figures 3A, 3B,
and 3C, indicate the cumulative event-free survival was
16 Roberts JACC Vol. 47, No. 1, 2006
Genomics and Cardiac Arrhythmias January 3, 2006:9–21

Figure 2. Schematic of inward and outward ionic currents, pumps, and exchangers that underlie atrial and ventricular action potentials in the mammalian
heart. Control and failing (bold line) action potential profiles are shown on top. Each phase of the action potential is labeled. Under the action potential,
a schematic of the time course of each current is shown, and the gene product (probable clone) that underlies the current is indicated. Reprinted with
permission from Fuster V, Alexander RW, O’Rourke RA. Hurst’s The Heart. 11th edition. McGraw-Hill Companies, 2004.

quite different among the three groups with the highest
event rate occurring in KCNH2 and SCN5A. Analysis for
gender within each subgroup showed that gender had no
influence on patients with a mutation in the KCNH2 gene,
whereas female patients with a mutation in the KCNH2
gene had a higher risk than male patients, and there was a
trend towards a higher risk among patients with a mutation
in the SCN5A. Thus, a first cardiac arrest or sudden death
was highest among female patients with a mutation in the
KCNH2 gene (0.82 per year) and male patients with a
mutation in the SCNA5 gene (0.96 per year). Thus, the role of
gender varies according to the genetic locus. Correcting for the
QT interval showed significant differences among the three
subgroups. The mean QT was 466 ⫾ 44 ms among patients
with a mutation at the KCNQ1 gene, 490 ⫾ 49 ms among
those with a mutation in the KCNH2 gene, and 496 ⫾ 49 ms
among those with mutations in the SCN5A gene. In each
subgroup, the QT interval was longer in those who were
symptomatic. The number of genetically affected patients with
a normal QT interval was significantly higher in the KCNQ1
group (36%) than in the KCNH2 group (19%) or the SCN5A
group (10%). Analysis of the event-free survival, taking into
account the quartile of corrected QT interval, showed progres-
sive decrease in survival at longer QTc values. These data
illustrate an interaction of the particular gene with gender and
the duration of the QT interval.
GENETIC IMPLICATIONS FOR THE
THERAPEUTIC MANAGEMENT OF LQTS
Despite the large number of mutations (300) responsible for
LQTS, there is still limited correlation with respect to specific
therapy. It is evident that mutations in the KCNH2 or
SCN5A genes are associated with more cardiac events. Given
the risk stratification provided by the three parameters previ-
ously discussed, the investigators (48,50) recommend that
prophylactic treatment is warranted in male and female pa-
tients with a mutation in the KCNQ1 gene who have a QT
above 500 ms or more, male patients with a mutation in the
KCNH2 gene who have a QT of 500 ms or more, all female
patients with a mutation at the KCNH2 gene irrespective of
the QT, and all patients with a mutation in the SCN5A gene.
Schwartz et al. (51,52) reported cardiac events more
frequently occur during exercise (62%) and only rarely
during sleep and rest in LQT1 patients. Swimming is also a
common trigger in the LQT1 syndrome (52). In contrast, in
LQT3 patients, cardiac events predominantly occur during
sleep and rest (39%) while exercise-induced events are rare
JACC Vol. 47, No. 1, 2006
January 3, 2006:9–21
Figure 3. Kaplan-Meier estimates of cumulative survival free of cardiac
events among the 580 patients with the long QT syndrome in the risk
stratification analysis, according to gender and the QT interval corrected
for heart rate (QTc), in the group with a mutation at the LQT1 locus (A),
the group with a mutation at the LQT2 locus (B), and the group with a
mutation at the LQT3 locus (C). Printed with permission from N Engl
J Med 2003;348:1866 –74.
(51). In LQT2 patients, cardiac events occur equally during
exercise or rest (51). Interestingly, a subtle startle in a form
of auditory stimulus is more likely to precipitate arrhythmias
in LQT2. Exercise or mental stress more often triggers
ventricular arrhythmias in LQT4 patients (49). In LQT7,
hypokalemia is more likely to trigger ventricular arrhythmias
as well as periodic paralysis. Thus, patients with these
Roberts 17
Genomics and Cardiac Arrhythmias
specific syndromes can be advised to avoid this form of
activity. Several studies have concluded that beta-blockers
are far more effective in LQT1 than LQT2 or LQT3.
Because it is more common to have a lethal event in LQT3
than in LQT1 or LQT2, some have suggested that an ICD
implantation is to be encouraged in patients with LQT3
syndrome (53). In 2002, Moss et al. (52) suggested LQT2
patients with mutations in the pore region of the KCNH2
gene have increased risk of arrhythmias over that of muta-
tions in the non-pore region. This has been disputed by
Zareba et al. (54), but a more recent Japanese study reports
findings similar to that of Moss et al. (55). Many patients
with LQTS do not respond to beta-blockers or other forms
of drug therapy and thus would be candidates for an ICD.
Nevertheless, in asymptomatic patients with borderline
prolonged QT, the decision remains difficult to insert an
ICD. The investigators strongly recommend that instituting
therapy in patients at low risk of becoming symptomatic
before the age of 40 years should be individualized. Further
studies are required in such patients before a robust recom-
mendation can be developed.
THE ROLE OF GENETICS IN DRUG-INDUCED LQTS
Long QT syndrome as a cause for ventricular tachycardia
and sudden death is more commonly associated with ac-
quired disorders than that of the familial LQTS. A major
cause of acquired long QT is drugs (56). The predominant
mechanism whereby the QT interval is prolonged, whether
it be genetic or acquired, is prolongation of sodium influx or
more commonly delayed outflux of potassium ions. There
are over 20 potassium channels expressed in the heart, most
of which participate in the AP (57). Antiarrhythmic drugs
can also induce long QT primarily those in class 1A (e.g.,
quinidine) or class 3 (e.g., sotolal). Of the 25 drugs for
which a mechanism has been elucidated, 24 of them are
blockers of the potassium channel, which delays repolariza-
tion. It is well recognized these drugs induce prolonged QT
only in individuals who are susceptible. It is the aim of
pharmacogenetics and pharmacogenomics to determine the
genetic basis for this susceptibility. One obvious avenue of
investigation is to determine whether these susceptible
individuals have a mutation in one of the channel proteins
that is aggravated by drugs. The extent to which this occurs
remains to be determined as screening for familial long QT
mutations remains experimental and time-consuming. A
recent study showed 10% to 15% of individuals with
drug-induced LQTS harbor ion channel gene mutations or
SNPs that predispose to the LQTS (58). Most of the
mutations or SNPs found so far that predispose to long QT
are in the potassium channels (59). Gene variants associated
with acquired arrhythmias according to Anantharam et al.
(60) can be classified as indirect, direct, and compound.
Indirect are mutations that impair the potassium channel at
baseline but do not affect drug sensitivity and are not
associated with any prolongation of the QT interval until
18 Roberts
Genomics and Cardiac Arrhythmias
drug administration is superimposed upon this inherited
impairment. An example would be A116V-MIRPI with
quinidine (61). Another example is an Asian-specific SNP
(G643S) in the KCNQ1 gene, which has been shown to
induce LQTS (62). The prevalence of G643S is 11% in the
Japanese population and was first identified after a patient
being on a class 1A antiarrhythmia agent. Another example
of an SNP predisposing to prolonged long QT, which
appears to be ethnic-related, is that of the S1102Y SNP
found more commonly in the African population (63). This
SNP in the SCN5A gene increases the risk of cardiac
arrhythmias in the presence of drugs such as amiodarone. It
is found primarily in West African, Caribbean, and African
American populations. It does not in itself cause LQTS but
only in the presence of other aggravating factors.
Direct mutations are perhaps the most difficult because
they do not affect potassium current but increase sensitivity
to drug blockade (64). An example of this is T8A-MIRPI
SNP present in 1.6% of the U.S. population was first
identified in a patient taking a combination of sulfamethox-
azole and trimethoprim. This SNP increases the sensitivity
of the sodium channel to blockage by the sulfa drugs. The
third category compound mutations are those that impair
channel function at baseline and also increase sensitivity to
the drug. An example is the Q9E MIRPI channel, which
was discovered in a female patient after taking clarithromy-
cin, which precipitated torsades de pointes. Women are
more vulnerable to develop prolonged QT than men if
caused by drugs that block the potassium channel (64).
Ultimately, if we are to avoid sudden death associated with
prolonged QT, it will be necessary to screen for all known
mutations and SNPs that predispose to long QT.
An equally fruitful area is the role of heredity with respect
to the pharmacokinetics of these drugs. Most of these drugs
are eliminated from the bloodstream by the cytochrome
CYP2D6 system in the liver which again, depending on
which particular polymorphism is inherited, can increase or
decrease the blood concentration of that particular drug.
Ultimately, it will be possible to determine whether some-
one is a rapid or slow acetylator of these drugs, and the
appropriate drug dose can be modified. It is well recognized
in the case of procainamide that fast acetylators of this drug
are less likely to develop the lupus syndrome (56). Similar
studies are well recognized for the development of neurop-
athy in response to isoniazid therapy (56).
SQTS
This is a rare disease associated with accelerated atrial and
ventricular depolarization and a high propensity for atrial and
ventricular arrhythmias (13). Mutations have been identified in
three genes, all of which are a gain-of-function. The syndrome
usually occurs in structurally normal hearts. The syndrome is
recognized by a short QT on the surface ECG. Three loci have
been identified referred to as SQTS1 and SQTS2 and SQTS3
(65); SQTS1 is caused by a gain-of-function mutation in the
JACC Vol. 47, No. 1, 2006
January 3, 2006:9–21
KCNH2 gene encoding an alpha subunit of the potassium
channel. The SQTS2 is caused by a gain-of-function mutation
in the KCNQ1 gene encoding the alpha subunit of the
potassium channel. The SQTS3 was reported recently (65) due
to a gain-of-function mutation in the KCNH2 gene encoding
for the inwardly rectifying potassium channel, which acceler-
ates repolarization and shortens the AP duration. It is of some
physiological significance that a loss of function mutation in
these genes is associated with the opposite effect, namely,
delayed repolarization, which induces familial LQTS. The
mechanism for arrhythmias in the SQTS is yet to be deter-
mined. The prevalence of the SQTS has, until recently, been
considered rare. There is increasing evidence that many cases
of ventricular fibrillation and SCD previously considered idio-
pathic may be due to SQTS. A rare disease referred to as
Anderson syndrome (66) is due to a loss-of-function mutation
in the gene encoding for a potassium channel subunit, which is
associated with muscle paralysis, long QT, and ventricular
arrhythmias. It is of interest that quinidine, a drug that
prolongs the QT interval, has been shown to favorably affect
this disease and is recommended as treatment to prevent
malignant arrhythmias.
FAMILIAL CATECHOLAMINERGIC
POLYMORPHIC VENTRICULAR TACHYCARDIA
This is inherited in autosomal dominant and recessive forms
occurring without evidence of structural myocardial disease
(67,68). It is characterized by bidirectional and polymorphic
ventricular tachycardia in response to vigorous exercise. This
frequently deteriorates into ventricular fibrillation and
death. Patients usually present with recurrent syncope,
seizures, or sudden death after physical activity or emotional
stress (69). The mortality is significant approximating 30%
by age 30 years (67,70). The first family was mapped to
1q42– 43 (67), and missense mutations were identified in
the gene encoding ryanodine receptor 2 (68). Subsequently,
mutations responsible for this disease were also shown to be
present in calsequestrin 2 (71). Thus, both genes are
involved with the release and handling of calcium.
The mechanism whereby these defects induce ventricular
tachycardia remains to be determined. It is well established
that the ectopic beats are initiated in discrete regions of the
epicardium. A recently proposed mechanism by Nam et al.
(72) suggests delayed afterdepolarization induces extrasys-
tolic activity, which triggers ventricular tachycardia under
conditions of defective calcium handling. The origin of the
ectopic beats in the epicardium increases transmural disper-
sion, which provides a substrate for re-entrant tachyarrhyth-
mias. The reason for the ectopics originating in the epicar-
dium is unknown but postulated to be because of the greater
density of sarcoplasmic reticulum calcium content in the
epicardium. The choice of treatment is a beta-blocker.
JACC Vol. 47, No. 1, 2006
January 3, 2006:9–21
TISSUE GENE PROFILING USING MICROARRAYS TO
SEARCH FOR GENES THAT INDUCE OR PREDISPOSE
TO VENTRICULAR AND ATRIAL ARRHYTHMIAS
The human genome is estimated to contain about 25,000
distinct genes. Identification of these genes and their func-
tion remains to be determined. Regulation of gene expres-
sion, recognized to play a major role in the response of the
body to environmental stimuli including disease, is of
critical importance in the diagnosis and treatment of disease.
Genetic regulation of organ differentiation is perhaps even less
understood. DNA or RNA microarray (73,74), a relatively new
technique consisting of thousands of genes etched into a chip,
can be used to identify genes via hybridization to complimen-
tary base pairing. Microarray chips are now available with
essentially all of the genes represented by expressed sequence
tag or oligonucleotide. This technique is being utilized to
determine which genes are expressed in certain tissues and the
extent to which their expression is regulated in response to a
variety of stimuli. It is well recognized in animal models and in
human disease that atrial fibrillation, once it occurs, tends to be
self-perpetuating and is associated with significant tissue re-
modeling of the atria (75). Studies being performed in the goat
(76) and in human atrial tissue removed at the time of surgery
(77) show a distinct gene expression profile associated with
atrial remodeling in response to atrial fibrillation. A variety of
genes have been observed to be up-regulated while others are
down-regulated during this remodeling process (78). It has also
been shown in animal models that once atrial fibrillation is
converted to sinus rhythm, this pattern will return to that of the
normal atrium (76). This provides an opportunity to assess
these genes for polymorphisms as well as perform genomic
function analysis to determine genes that play a pathogenic role
in sustaining atrial fibrillation. Such studies, while in their
primitive state, are ongoing. Another area of interest is atrial
fibrillation that occurs after cardiac surgery in about 20% of
individuals (77). Are they predisposed to genetic factors? The
ability to scan with a chip containing 25,000 genes should
accelerate finding genes pivotal to the disease.
Similarly, it is well recognized that ventricular hypertrophy
increases one’s risk of sudden death two- to four-fold regardless
of the stimulus (18). The mechanism whereby ventricular
hypertrophy increases risk to arrhythmias have not been deter-
mined. It is thus reasonable to assume that certain genes with
polymorphisms that predispose to sudden death may be up-
regulated in hypertrophy, which accounts in part for the
vulnerability to arrhythmias. Microarray analysis, again, has
already shown there is a differential display of genes in the atria
and ventricle, and with the development of hypertrophy the
fetal program of genes is up-regulated along with a variety of
other genes (18). The microarray also provides the opportunity
to classify genes in clusters as well as identify sets of genes that
play a role in cell signaling. Thus, if a particular gene with an
SNP is shown to be important, one can assess for SNPs in
other such genes that are part of the signaling network.
Nevertheless, it will significantly accelerate our ability to relate
Roberts 19
Genomics and Cardiac Arrhythmias
and associate genes with certain responses to the environment
such as remodeling with atrial fibrillation or hypertrophy in
response to ischemic heart disease.
FUTURE OF GENOMICS IN
CARDIOVASCULAR ARRHYTHMIAS
While cardiac arrhythmias may be associated with or
without structural heart disease, the defect always involves
some aspect of the electrical conduction system of the heart.
The structural component is, of course, the sinus node,
specialized atrial tracts, atrioventricular node, and bundle of
HIS with the Purkinje system. After conducting within this
specialized electrical transmission, the current must pass
into other cells such as myocytes. The important compo-
nents are predominantly ionic currents, ion channels, struc-
tural proteins, and gap junctions. Most of the genetic
defects currently identified involve some aspect of the
subunits of the ion channels. We now recognize at least 429
genes that encode ion channel proteins in the human (79).
Of these, 170 encode potassium channels, 38 are for calcium
channels, 29 are for sodium channels, 58 are for chloride
channels, and 15 are glutemate receptors (80). It is of
interest that ion channels represent only about 5% of the
molecular targets of modern medicine (81,82). It is now
recognized that in addition to the role of ion channels
regulating membrane potential they also regulate many
other functions including cell volume and hormone secre-
tion (83,84). The complexity of these channels, such as the
voltage-gated cardiac potassium channels, is such that
several domains exist within the integrated channel protein.
In addition to the pore domain, there are the domains that
provide ion selectivity, opening and closing of the gate
together with the sensing units whether it be voltage or
chemical. The elucidation of mutations causing disease is
rapidly enhancing our understanding of the topography and
sequences involved with each domain. Approaches by the
pharmaceutical industry to develop designer drugs for those
domains, while in its infancy, are rapidly developing.
The characteristic feature of the electrical activity of the
heart is the AP of the atria and ventricles due to depolar-
ization and repolarization with the characteristic long pla-
teau phase involving multiple ion channels. Many of these
channels have now been cloned and will serve as prime
candidates for the identification of genetic defects in the
future. The major currents involved in the atrial and
ventricular AP are indicated in Figure 2. Cardiac electrical
activity is thus a complex process, which integrates the
electrical activity of multiple molecules. Any variant in
either of these molecules whether it is due to SNPs or
greater defects can significantly alter cardiac activity. It is
well recognized that structural heart disease, associated with
either hypertrophy or cardiac dilatation, can structurally
affect electrical transmission or through altered gene expres-
sion induce arrhythmias. Hypertrophy is well documented
to increase the propensity for SCD by about four-fold.
20 Roberts
Genomics and Cardiac Arrhythmias
Structural heart disease is associated with excessive fibrous
tissue, which has a lower velocity of conduction and could
lead to re-entry arrhythmias. Common genetic variants have
been shown to increase the risk of cardiac arrhythmias, and
most recent studies show that even common genetic variant
in genes referred to as SNPs can alter cardiac electrical
manifestations in certain populations. Atrial fibrillation is
associated with significant morbidity in the aging popula-
tion. Ventricular fibrillation is a lethal arrhythmia respon-
sible for over 600,000 deaths each year in the Western
world. Both atrial and ventricular fibrillation remain the
most challenging of rhythm disorders.
Reprint requests and correspondence: Dr. Robert Roberts,
University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa,
Ontario, K1Y 4W7 Canada. E-mail: rroberts@ottawaheart.ca.
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