THE ANATOMICAL RECORD PART A 280A:934 –939 (2004)

Genetics of Atrioventricular
Conduction Disease in Humans
D. WOODROW BENSON*
Division of Cardiology, Children’s Hospital Medical Center, Cincinnati, Ohio

ABSTRACT
Atrioventricular (AV) conduction disease (block) describes impairment of the electrical
continuity between the atria and ventricles. Classification of AV block has utilized biophys-
ical characteristics, usually the extent (first, second, or third degree) and site of block (above
or below His bundle recording site). The genetic significance of this classification is unknown.
In young patients, AV block may result from injury or be the major cardiac manifestation of
neuromuscular disease. However, in some cases, AV block has unknown or idiopathic cause.
In such cases, familial clustering has been noted and published pedigrees show autosomal
dominant inheritance; associated heart disease is common (e.g., congenital heart malforma-
tion, cardiomyopathy). The latter finding is not surprising given the common origin of
working myocytes and specialized conduction system elements. Using genetic models incor-
porating reduced penetrance (disease absence in some individuals with disease gene), vari-
able expressivity (individuals with disease gene have different phenotypes), and genetic
heterogeneity (similar phenotypes, different genetic cause), molecular genetic causes of AV
block are being identified. Mutations identified in genes with diverse functions (transcription,
excitability, and energy homeostasis) for the first time provide the means to assess risk and
offer insight into the molecular basis of this important clinical condition previously defined
only by biophysical characteristics. © 2004 Wiley-Liss, Inc.

Key words: ion channels; transcription factors; human genetics; heart block;
pediatrics; gene mutation; congenital heart disease

The atrioventricular (AV) conduction system is com-
prised of specialized cells that permit synchronized car-
diac excitation resulting in contraction of the atria during
ventricular filling and rapid depolarization of the ventri-
cles. In the postnatal heart, distinguishable anatomic
components of the AV conduction system include the si-
noatrial node, AV node, and His bundle and left and right
bundle branches and Purkinje ramifications. These ele-
ments are distinct from the ordinary working myocar-
dium, and much has been learned of the developmental,
anatomic, electrophysiologic, and gene expression charac-
teristics of the conduction system components (Gourdie et
al., 1999; Thomas et al., 2001; Moorman and Christoffels,
2003).
ATRIOVENTRICULAR CONDUCTION
DISEASE: AN ELECTROANATOMIC MODEL
Much of our understanding of AV conduction disease is
the result of detailed anatomic studies correlated with
comprehensive electrocardiographic and electrophysi-
ologic characterization of the conduction system. Normal
impulse initiation begins in the sinoatrial node, then trav-
els through the atrium before reaching the AV node in the
lower intra-atrial septum. The impulse conducts through
the AV node to the His bundle, which divides into the right
and left bundles distributing the impulse to the right and
left ventricles, respectively. AV conduction disease may
manifest from conduction slowing or complete block any-
where along the path.
An electroanatomic classification of AV conduction dis-
ease is widely used clinically and is based on the extent
(first, second, or third degree) of block and the site within
the conduction system of block (Fig. 1). In large measure,
this AV block classification is based on characteristics of
the PR interval (time interval from onset of P-wave to
onset of QRS complex) on the surface electrocardiogram.
In some instances, AV conduction disease has been de-
Grant sponsor: National Institute of Child Health & Human
Development (NICHD); Grant number: HD39946.
*Correspondence to: D. Woodrow Benson, Division of Cardiol-
ogy, ML7042, Children’s Hospital Medical Center, 3333 Burnet
Avenue, Cincinnati, OH 45229. Fax: 513-636-5958.
E-mail: woody.benson@cchmc.org
Received 15 April 2004; Accepted 20 June 2004
DOI 10.1002/ar.a.20099
Published online 15 September 2004 in Wiley InterScience
(www.interscience.wiley.com).

© 2004 WILEY-LISS, INC.


GENETICS OF AV CONDUCTION
Fig. 1. Electroanatomic classification of AV conduction disease. A,
B, and C illustrate first-, second-, and third-degree heart block, respec-
tively. D illustrates division of the PR interval into three subintervals that
are related to conduction in specific anatomic sites; identification of the
subintervals requires simultaneous recording of the surface electrocar-
diogram and intracardiac recording of the His bundle potential. The
subintervals are termed the PA interval (intra-atrial conduction), AH
interval (AV node conduction), and HV interval (distal His-Purkinje con-
duction). Sites of block, relative to intracardiac recording of the His
bundle electrogram (HBE), are depicted. AH, conduction interval from
onset of low septal atrial depolarization to His bundle spike (H) to onset
of ventricular depolarization; HV, conduction interval from onset of His
spike to onset of ventricular depolarization; PA, conduction interval from
onset of P-wave to low atrial septal depolarization.
scribed as progressive if the electrocardiographic charac-
terization of AV conduction worsens over time, e.g., block
progresses from second to third degree.
First-degree AV block manifests as prolongation of the
PR interval, indicating mild conduction delay. In the most
severe form, designated third-degree or complete AV
block, no atrial impulses conduct to the ventricle; on the
electrocardiogram, QRS complexes occur independent of
P-waves. Second-degree AV block is an intermediate form,
and some atrial impulses are conducted to the ventricle;
electrocardiographic manifestation is association of some
QRS complexes with P-waves. Second-degree block is fur-
ther classified as type 1 or type 2. In type 1 block, progres-
sive prolongation of the PR interval is observed before the
occurrence of AV block (Wenckebach periodicity). In type
2, the block occurs abruptly without PR interval prolon-
gation.
The PR interval can be subdivided into three subinter-
vals, which are related to conduction within specific ana-
tomic sites (Fig. 1); this anatomic characterization of AV
conduction permits determination of the anatomic site of
block. For example, using this approach, type 1 second-
degree block, considered benign, usually results from
block in the AV node (supra-Hisian block), while type 2
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935
second-degree AV block usually results from block in the
distal His-Purkinje system (infra-Hisian block) and is as-
sociated with risk of sudden demise. While the classifica-
tion of AV block by the extent of block, the site of block,
and progressive nature has been useful in patient man-
agement for guiding the indications for pacing therapy,
the genetic significance of this classification scheme is not
known.
WHAT IS KNOWN OF ETIOLOGY OF AV
CONDUCTION DISEASE
An association between AV conduction disease and myo-
cardial injury due to infarction has long been known (Ap-
lin et al., 2003). The occurrence of AV block as a surgical
complication was recognized early in the open heart sur-
gery experience, but with improved understanding of AV
conduction system anatomy the incidence of this compli-
cation for cardiac surgery has been reduced. Most surgi-
cally induced AV block is the consequence of procedures
involving valve replacement or closure of atrioventricular
or ventricular septal defects, and when noted immediately
after surgery or early in the postoperative period, block is
thought to result from trauma to the conduction system
(Ho et al., 1985; Limongelli et al., 2003). However, AV
block identified late in the postoperative period may be
another phenotypic manifestation of the heart disease and
thereby attributable to a gene mutation rather than a
surgical complication (Benson et al., 1999).
AV block associated with transplacental passage of ma-
ternal antibody is hypothesized to result from injury to the
developing conduction system. Nearly 3 decades ago, it
was noted that mothers who gave birth to children with
AV block often had autoimmune diseases (McCue et al.,
1977; Buyon et al., 1998). It is now well established that
AV block detected before or at birth, in the absence of
other cardiac malformation, is strongly associated with
maternal autoantibodies to SSA/Ro and/or SSB/La ribo-
nucleoproteins, independent of whether the mother has
systemic lupus erythematosus or Sjogren’s syndrome or is
totally asymptomatic (Buyon et al., 1998; Moak et al.,
2001). Antibody-associated AV block is most often de-
tected between 16 and 24 weeks of gestation in an other-
wise normal heart and is considered a consequence of
transplacental passage of autoantibodies into the fetal
circulation resulting in tissue injury. Maternal antibody-
associated AV block is irreversible, carries a substantial
mortality (approaching 30%) and morbidity, with ⬎ 60% of
affected children requiring lifelong pacemakers (Buyon et
al., 1998). The target antigens (48 kD SSB/La, 52 kD
SSA/Ro, and 60 kD SSA/Ro) have been extensively char-
acterized, but pathogenicity remains to be clarified.
AV CONDUCTION DISEASE AND
NEUROMUSCULAR DISORDERS
AV conduction disturbance is usually the major cardiac
manifestation of neuromuscular diseases, including Em-
ery-Dreifuss muscular dystrophy, Kearns-Sayre syn-
drome, and myotonic dystrophy. AV block can be an im-
portant cause of mortality in such cases, and recognition
of this possibility is important since pacemaker implanta-
tion can be life-saving.
Emery-Dreifuss muscular dystrophy occurs as an X-
linked trait, caused by emerin mutations (Bione et al.,
1994; Nagano et al., 1996) or as an autosomal dominant

936 BENSON
disorder resulting from mutations in the gene encoding
lamins A and C (Bonne et al., 1999). Like emerin, lamins
A and C are components of the nuclear envelope but are
located in the lamina, a multimeric structure associated
with the nucleoplasmic surface of the inner nuclear mem-
brane. Conduction system disease is caused by defects in
the head or tail domain of the lamin gene or by emerin
mutations (Fatkin et al., 1999); conduction abnormalities
are progressive and occur at sites throughout the conduc-
tion system. The mechanism by which lamin A/C muta-
tions cause Emery-Dreifuss muscular dystrophy is un-
known, but defining how these mutations alter cardiac cell
biology should increase our understanding of the patho-
genesis of AV block.
Kearns-Sayre syndrome is a mitochondrial disorder
characterized by progressive external ophthalmoplegia,
retinal pigmentation, and cardiac conduction abnormality
that onsets during childhood to adolescence. The Kearns-
Sayre syndrome phenotype is usually associated with mi-
tochondrial DNA deletions (Moraes et al., 1989; Anan et
al., 1995). However, the genotype-phenotype correlation of
mitochondrial DNA mutations is complex and inexact,
and the precise relation between clinical and biochemical
phenotypes and deletions remains to be defined (Ashizawa
and Subramony, 2001). Reported cases of Kearns-Sayre
syndrome are typically isolated with a normal family his-
tory in spite of predicted maternal inheritance (Anan et
al., 1995; DiMauro and Schon, 2001). Two possible expla-
nations are usually given. First, since mtDNA is more
susceptible than nuclear DNA to mutations, some dele-
tions may be new mutations that occurred sporadically
during development. Alternatively, mothers of affected
patients may carry a subthreshold number of defective
mitochondria (Ashizawa and Subramony, 2001). The AV
block seen in Kearns-Sayre syndrome is both progressive
and infra-Hisian.
Myotonic dystrophy is an autosomal dominant disorder
characterized by myotonia, muscular dystrophy, and de-
velopment of AV conduction disturbances. In 1992, a dis-
ease-causing trinucleotide (CTG) repeat was identified on
chromosome 19q13 (Brook et al., 1992). The CTG repeat is
transcribed and is located in the 3⬘ untranslated region of
an mRNA that is expressed in tissues affected by myotonic
dystrophy. This sequence is highly variable in the normal
population, and normal individuals have between 5 and 27
copies. On the other hand, myotonic dystrophy patients
have at least 50 repeats (mildly affected) to as many as
2,000 or more copies (severely affected). A cardiac conduc-
tion phenotype is common and there has been consider-
able interest in its relationship to genotype (extent of CTG
expansion). Studies to date suggest that CTG length is
correlated with the age at onset of electrocardiographic
abnormalities (Antonini et al., 2000). The AV block seen in
myotonic dystrophy is both progressive and infra-Hisian;
conduction system histology reveals fibrosis, fatty infiltra-
tion, and atrophy and electrophysiologic studies demon-
strate diffuse conduction abnormality (Prystowsky et al.,
1979; Nguyen et al., 1988).
IDIOPATHIC AV CONDUCTION DISEASE
In some cases, an obvious cause of AV conduction dis-
ease is not identifiable. Familial clustering of AV block of
unknown or idiopathic cause has been recognized, and
published pedigrees show autosomal dominant inheri-
tance (Brink et al., 1995). Some individuals with AV con-
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duction disease have a health history or family history of
other forms of cardiovascular disease in the young, includ-
ing cardiomyopathy or congenital cardiac anomaly. The
genetic significance of these associations is not completely
understood, but such findings are not unanticipated given
the common origin of the specialized conduction system
elements and the working myocardium (Gourdie et al.,
1999; Takebayashi-Suzuki et al., 2001). An increasing
number of entries in Online Mendelian Inheritance in
Man (OMIM) are indications of the increasing frequency
with which single genes that cause AV conduction disease
are being recognized (genetic heterogeneity). Elucidation
of the genetic basis of AV block has required genetic mod-
els that utilize reduced penetrance (presence of disease
genotype in absence of phenotype) and variable expressiv-
ity (presence of a disease genotype with variable pheno-
types).
AV CONDUCTION DISEASE AND
CONGENITAL CARDIAC MALFORMATIONS
An association between AV conduction abnormalities
and congenital cardiac abnormalities has long been ob-
served. Recently, heterozygous mutations in the cardiac-
specific transcription factor, NKX2.5, were identified as a
cause of both AV conduction disease and varied congenital
cardiac malformations (Schott et al., 1998; Benson et al.,
1999; Goldmuntz et al., 2001; Watanabe et al., 2002;
McElhinney et al., 2003). Based on previous studies in fly
and mouse, these findings were unexpected. For NKX2.5
mutations, the spectrum of cardiac malformations in-
cludes atrial septal defect, ventricular septal defect, te-
tralogy of Fallot, and tricuspid valve abnormalities, in-
cluding Ebstein malformation, but the AV block
phenotype develops even in the absence of associated mal-
formation (Benson et al., 1999; Pashmfaroush et al.,
2004). Mutations that markedly reduce DNA binding are
most likely to result in the AV conduction disease pheno-
type (Kasahara et al., 2000; Kasahara and Benson, 2004);
these include nonsense mutations and missense muta-
tions in the homeodomain (Fig. 2). In individuals with
NKX2.5 mutation, AV block is due to AV node conduction
delay that progresses during postnatal life such that most
individuals have advanced second-degree or third-degree
AV block by the third decade of life (Benson et al., 1999).
The developmental basis for the progressive AV conduc-
tion disease, which is similar to that observed in associa-
tion with heterozygous TBX5 (a t-box transcription factor)
mutations (Basson et al., 1997), has not been elucidated.
AV CONDUCTION DISEASE, VENTRICULAR
HYPERTROPHY, AND WOLFF-PARKINSON-
WHITE SYNDROME
Mutations in PRKAG2, the gene for the ␥2 regulatory
subunit of AMP-activated protein kinase, cause ventricu-
lar preexcitation (Wolff-Parkinson-White syndrome) and
AV conduction block (Arad et al., 2002). Affected individ-
uals also manifest cardiac hypertrophy, and while the
cardiac pathology caused by PRKAG2 mutations includes
myocyte enlargement and minimal interstitial fibrosis,
the characteristic features of hypertrophic cardiomyopa-
thy are absent. Thus, PRKAG2 mutations appear to result
in a novel myocardial storage disease characterized by
formation of vacuoles filled with glycogen-associated gran-
ules within myocytes. Detailed clinical electrophysiology

GENETICS OF AV CONDUCTION
Fig. 2. NKX2.5 mutations and AV conduction disease. The relative
location of 28 NKX2.5 mutations are depicted on the cartoon. Home-
odomain missense mutations and nonsense mutations predicted to
result in a truncated protein, shown above the cartoon, are associated
studies of this phenotype have shown that accessory AV
connections are responsible for preexcitation, and the elec-
trophysiologic properties and locations of these AV con-
nections are similar to those reported in isolated cases of
Wolff-Parkinson-White syndrome (Arad et al., 2002). The
AV block is progressive and the site of block is in the distal
His-Purkinje system (below the His bundle recording site)
(Fig. 1). Accumulation of glycogen-associated granules in
conductive tissue may lead to AV conduction disturbance,
but disruption of the annulus fibrosis by glycogen-en-
gorged myocytes is the cause of preexcitation in this gly-
cogen storage cardiomyopathy (Arad et al., 2003).
AV CONDUCTION DISEASE IS A
CHANNELOPATHY
Two distinct inherited syndromes of cardiac arrhyth-
mia, the congenital long QT syndrome and Brugada syn-
drome, have been previously associated with mutations in
the cardiac voltage-gated sodium channel ␣-subunit gene
(SCN5A). Mutations resulting in long QT syndrome cause
persistent sodium current and delay repolarization,
thereby predisposing to the distinctive polymorphic ven-
tricular tachycardia, torsades de pointes. SCN5A muta-
tions associated with Brugada syndrome reduce sodium
current, alter transmural myocardial voltage gradients,
and increase the risk for ventricular fibrillation. Recently,
heterozygous SCN5A mutations were detected in individ-
uals with AV block, thus identifying a third cardiac so-
dium channelopathy (Fig. 3) (Schott et al., 1999; Tan et
al., 2001; Wang et al., 2002; Viswanathan et al., 2003).
Biophysical characterization of AV block-causing
SCN5A mutation revealed distinct gating abnormalities
not previously observed for other SCN5A alleles (Tan et
al., 2001; Wang et al., 2002; Viswanathan et al., 2003). In
heterologous expression studies, AV block-causing SCN5A
mutations demonstrate varied competing gating effects
that result in reduced levels of sodium current density,
leading to the speculation that a similar reduction may
occur in vivo. Reduced myocardial sodium current density
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937
with AV conduction disease. Missense mutations in the amino- or car-
boxyterminus (excluding the homeodomain), shown below the cartoon,
do not demonstrate this aspect of the phenotype.
Fig. 3. Diagram of SCN5A mutations causing AV block. Six previ-
ously reported mutations are shown on a cartoon of SCN5A (Schott et
al., 1999; Tan et al., 2001; Wang et al., 2002; Viswanathan et al., 2003).
The common SCN5A polymorphism (H558R), located on the I–II inter-
domain cytoplasmic linker and present in 20% of the population, miti-
gates the in vitro effects of a nearby mutation (T512I) on sodium channel
function. T512I and H558R were both found on the same allele of a child
with isolated conduction disease, suggesting a direct functional associ-
ation between a polymorphism and a mutation in the same gene
(Viswanathan et al., 2003).
will slow the rise time of the cardiac action potential and
slow conduction velocity, resulting in conduction abnor-
mality rather than another arrhythmia phenotype. Based
on the limited studies performed to date, AV block due to
SCN5A mutation is progressive and both supra-Hisian
and infra-Hisian block have been observed.
In the taxonomy of clinical electrophysiology, arrhyth-
mias related to malfunction of the sinus node are usually
regarded differently than those related to malfunction of
the AV node, His bundle, and distal conduction system
elements. However, recent findings that some forms of
congenital sick sinus syndrome, characterized by brady-
cardia progressing to atrial inexcitability during the first
decade of life, define a recessive disorder of a human heart
voltage-gated sodium channel, thereby providing a link
between these seemingly disparate electrophysiological
phenotypes. SCN5A mutants associated with congenital

938 BENSON
sick sinus syndrome demonstrate loss of function or sig-
nificant impairments in channel gating (inactivation) that
predict reduced myocardial excitability (Benson et al.,
2003).
Andersen-Tawil syndrome (ATS) is a heterogeneous au-
tosomal dominant or sporadic disorder resulting in cardiac
arrhythmias, periodic paralysis, and/or dysmorphic fea-
tures. Mutations of KCNJ2 cause type 1 Andersen-Tawil
syndrome (ATS1) and over 20 mutations have been iden-
tified (Plaster et al., 2001; Andelfinger et al., 2002;
Tristani-Firouzi et al., 2002; Zhang et al., 2004). KCNJ2
encodes the inward rectifier Kir2.1, a member of the
Kir2.x subfamily and a critical component of cardiac IK1,
the inward potassium rectifier current. KCNJ2 mutations
identified to date cause loss of function and dominant-
negative suppression of the Kir2.1 channel function. In a
study of ECG data from 96 KCNJ2 mutation carriers
derived from 33 unrelated families, no significant differ-
ence was found in heart rate, PR interval, or QRS dura-
tion between ATS1 patients and normal subjects. In addi-
tion, the mean QTc was within the upper normal range
(439 ⫾ 26 msec); 64% of mutation carriers had a QTc ⱕ
440 msec and only 17% had a QTc ⬎ 460 msec. However,
21% (20/96) of ATS1 patients in nine families showed
conduction abnormalities, including first-degree AV block
(seven), right bundle branch block (seven), left bundle
branch block (two), bifascicular block (two), and intraven-
tricular conduction delay (two).
CONCLUSION
Considerable progress has been made in the diagnosis
and treatment of AV conduction disease, but little has
been known of the cause of this important clinical problem
and many cases have been considered to be idiopathic.
Recently, molecular genetic causes of viable AV block have
been identified, and autosomal dominant inheritance with
reduced penetrance and variable expressivity is recog-
nized most often. AV block-causing mutations identified to
date result in progressive conduction system disease in-
volving various sites within the conduction system. These
findings are significant, since they provide insight into the
molecular basis of an important clinical condition previ-
ously defined only by biophysical characteristics.
For the electrophysiologist, understanding the mode of
inheritance is essential for identifying individuals at risk
of developing AV block. For the molecular geneticist, pat-
terns of transmission can direct strategies for identifica-
tion of the disease-causing gene mutation. For the devel-
opmental biologist, disease-causing mutations become
reagents for dissecting the processes whereby cells from
common ancestry are recruited into the atrium, ventricle,
or conduction system and the tubular embryonic heart is
transformed into the four-chambered adult heart.
Models of AV block pathophysiology, based on electro-
cardiographic and electrophysiologic characteristics, have
been useful for diagnosis and treatment of affected indi-
viduals, but identification of genes causing AV block prom-
ises to lead to improved understanding of the pathophys-
iologic basis and natural history. Establishing the
genotype of individuals with AV block phenotypes will
provide an unambiguous way to identify siblings, off-
spring, and other genotype-positive family members at
risk for developing AV block. Based on progress to date,
improved understanding of pathophysiology will lead to
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alternative diagnostic methods and new therapeutic strat-
egies for these common and challenging clinical problems.
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