REVIEW

A Review on Advanced Atrioventricular Block in Young

or Middle-Aged Adults
SÉRGIO NUNO CRAVEIRO BARRA, M.D., RUI PROVIDÊNCIA, M.D., M.Sc., LUÍS PAIVA,
M.D., M.Sc., JOSÉ NASCIMENTO, M.D., and ANTÓNIO LEITÃO MARQUES, M.D.
From the Cardiology Department, Coimbra Hospital and University Centre, Centro Hospitalar de Coimbra, Coimbra,
Portugal

Complete atrioventricular block is a relatively uncommon arrhythmia that is nonetheless increasingly

seen in elderly people of developed countries, due to the increase in life expectancy. Congenital and
degenerative etiologies are the most commonly seen among young and old patients, respectively. However,
scientific literature is surprisingly scarce regarding the etiology of complete atrioventricular block in
the asymptomatic otherwise healthy young and middle-aged adult population. Coronary artery disease,
autoimmune disorders such as systemic lupus erythematosus or rheumatoid arthritis, history of acute
or chronic infectious or hypersensitivity myocarditis, infiltrative processes, hypothyroidism, congenital
cardiopathies such as left ventricular noncompaction or Ebstein anomaly, lamin A/C mutations,
and pathologic hypervagotony and idiopathic degenerative scleroatrophy of the atrioventricular
junctional specialized tissue (Lenegre-Lev disease) are among the most frequent etiologies of complete
atrioventricular block in young or middle-aged adults. To our knowledge, no comprehensive review on
the specificities of the investigation warranted in this age group has ever been developed, nor have the
implications of particular diagnoses on treatment modalities been appropriately addressed. We aim at
reviewing the most frequent differential diagnoses of advanced atrioventricular block in otherwise healthy
asymptomatic or mildly symptomatic young or middle-aged adults and their impact on therapeutic
options. Additionally, we suggest a diagnostic algorithm that may be helpful in this group of patients.
(PACE 2012; 00:1–11)
complete atrioventricular block, atrioventricular block etiology, cardiac conduction

Introduction complete AV block. This latter form of heart

Complete heart block, also referred to as third-
degree heart block or third-degree atrioventricular
(AV) block, is a disorder of the cardiac conduction
system where there is complete dissociation of the
atrial and ventricular activity due to the absence
of conduction through the atrioventricular node
(AVN) or His-Purkinje system. Although Mobitz
I second-degree AV block is observed in 1–2% of
healthy young people, especially during sleep, the
prevalence of third-degree AV block is only 0.02%
in the United States and 0.04% worldwide.1,2 Its
incidence increases with advancing age (highest in
people older than 70 years), despite an early peak
in infancy and early childhood due to congenital
Conflicts of interest: None.
Financial support: None.
Address for reprints: Sérgio Nuno Craveiro Barra, M.D., R.
António F. Fiandor 112 – 4 Dto, 4430–017 V. N. Gaia, Portugal.
E-mail: sergioncbarra@gmail.com
Received March 27, 2012; revised May 12, 2012; accepted June
11, 2012.
doi: 10.1111/j.1540-8159.2012.03489.x
block occurs in one out of each 20–22,000 births,
usually associates with maternal antibodies to Ro
(SS-A) and La (SS-B) and maternal lupus, and
shows a 60% female preponderance (against a
60% male preponderance for acquired complete
heart block).3
Acquired AV block results from various
pathologic states causing infiltration, fibrosis, or
loss of connection in portions of the healthy
conduction system. The underlying condition
strongly influences both the age of presenta-
tion/onset and the prognosis. To the best of
our knowledge, no comprehensive review on the
specificities of the investigation warranted in oth-
erwise healthy young or middle-aged adults with
complete asymptomatic or mildly symptomatic
AV block has ever been developed, nor have the
implications of particular diagnoses on treatment
modalities been appropriately addressed. Thus,
this review presents a description of the most
frequent differential diagnoses and etiologies
of complete AV block in young or middle-
aged asymptomatic adults and describes their
impact on subsequent therapeutic measures. In
addition, the authors suggest a potential diagnostic
algorithm for this group of patients.

C 2012, The Authors. Journal compilation 

 C 2012 Wiley Periodicals, Inc.

PACE, Vol. 00 2012 1

 BARRA, ET AL.
It is beyond the scope of this review to
describe or summarize acute iatrogenic forms
of complete heart block resulting from isolated
single-agent drug overdose or combined co-
administration of AV nodal blocking agents,
AV block associated with aortic valve surgery,
septal alcohol ablation, percutaneous coronary
interventions, or electrophysiology ablation of the
slow or fast pathway of the AVN. Also, as we
focus mainly on otherwise healthy asymptomatic
young or middle-aged adults, no references will be
made to complete AV block associated with acute
cardiovascular conditions such as myocardial
infarction (MI) or cardiogenic shock. Congenital
heart block will not be thoroughly revised, as
most cases present in infancy or early childhood.
The etiologies presented in this review are
compatible with advanced AV nodal conduction
abnormalities as form of presentation.
Differential Diagnoses
Third-degree AV block can be either con-
genital or acquired. Table I lists the most
common potential causes of acquired advanced
AV block in otherwise healthy young or middle-
aged adult patients, whereas Table II lists rarer
etiologies.
In most of these conditions, atrioventricular
conduction abnormalities are occasionally the
first sign of the disease. Patients may present at
Table I.
Most Common Causes of Advanced Atrioventricular
Block in Otherwise Healthy Young or Middle-Aged
Individuals
Coronary artery disease
Degenerative diseases: Lenegre (sclerodegenerative
process involving the conduction system only) and Lev
diseases (calcification of the conduction system and
valves), mitochondrial myopathy
Nonischemic cardiomyopathies – De novo or familial
dilated cardiomyopathy
Infectious causes – Lyme borreliosis, Trypanosoma cruzi
infection, rheumatic fever, myocarditis, Chagas
disease, Aspergillus myocarditis, varicella-zoster virus
infection
Rheumatic and autoimmune diseases – Giant-cell
myocarditis, ankylosing spondylitis, rheumatoid
arthritis, systemic sclerosis, systemic lupus
erythematosus
Infiltrative processes – Amyloidosis, sarcoidosis, tumors,
Non-Hodgkin lymphoma, multiple myeloma
Vagally induced
Iatrogenic causes (including drugs)
2 2012
Table II.
Very Rare Causes of Advanced Atrioventricular Block in
Otherwise Healthy Young or Middle-Aged Individuals
Neuromuscular or neurologic disorders – Becker
muscular dystrophy, myotonic muscular dystrophy,
scapuloperoneal dystrophy, oculocraniosomatic
syndrome
Metabolic causes – Hypoxia, hyperkalemia, thyroid
disorders
Phase IV idiopathic block
Radiation-induced
Psychiatric conditions
Unexplained apoptosis of the cardiac conduction system
Acute rheumatic fever
Left ventricular noncompaction
Thyroid disorders
the Cardiology outpatient clinic with a baseline
electrocardiogram (ECG) or a 24-hour Holter
revealing periods of advanced atrioventricular
block despite the absence of significant symptoma-
tology. Often, patients are submitted to pacemaker
implantation with no further investigation, which
comprehensively delays an objective diagnosis
and appropriate therapy for the baseline condi-
tion.
For simplification purposes, each major eti-
ologic group will be addressed in its respective
topic.
Coronary Artery Disease
Acute heart block is an uncommon but
serious complication of MI. Chronic heart block
associated with Stokes-Adams attacks has been
often assumed to be ischemic in origin as well,
and factors supporting its importance were the not
uncommon precipitation of acute heart block by
myocardial infarction or acute ischemia and elec-
trocardiographic evidence of changing T waves
in patients carrying pacemakers which would not
be recognized as simply occurring secondary to
pacing. Nevertheless, some studies have stressed
the high incidence of primary heart block in
patients with coronary artery disease (CAD). The
incidence of CAD as a cause of chronic heart block
in the elderly was studied at necropsy by Davies
et al. This author found that only 15% of studied
patients had CAD of sufficient severity to account
for the heart block (destruction of both bundle
branches in areas of old infarctions).4 Bundle-
branch fibrosis of unknown etiology, without
major damage to the contractile myocardium,
was the most common cause, which explained
the relatively normal expectation of life once
paced.5 The CARISMA study was the first one to
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 ATRIOVENTRICULAR BLOCK IN YOUNG ADULTS
report on long-term cardiac arrhythmias recorded
by an implantable loop recorder in patients
with left ventricular ejection fraction ≤40% after
myocardial infarction. A 10% incidence of high-
degree AV block (≤30 beats per minute lasting
≥8 seconds) was reported during a 1.9 ± 0.5 year
follow-up.6
Subsequent studies have focused on the
relatively poor prognosis of middle-aged patients
paced for chronic AV block when age-linked
expectation of life was taken into account,
suggesting this could result from underlying CAD
even in the absence of symptoms suggesting this
diagnosis. Ginks et al. examined a consecutive
series of 30 patients aged 45–65 with chronic
AV disease who had been referred for pacing.
Coronary arteriography disclosed the presence
of severe coronary artery disease in 13 patients
(43.3%) and a close relation between the level
of heart block and the distribution of the CAD
(right coronary artery lesions would cause nodal
ischemia and conduction delay proximal to the
bundle of His, while left anterior descending
occlusion would cause bundle branch ischemia
and delayed conduction distal to the bundle of
His).7
Subsequent studies have demonstrated the
relationship between atrioventricular conduction
abnormalities and CAD. Brueck et al. suggested
patients with severe AV conduction disturbances
or sinus node dysfunction requiring permanent
pacemaker implantation were more likely to
have CAD with subsequent need for myocardial
revascularization in the presence of at least one
atherosclerotic risk factor.8 Tandogan et al. have
shown that the presence of first perforator and
right coronary artery (RCA) lesions with poor
quality of flow shown angiographically should
be considered major risk factors for the need of
permanent pacemaker implantation in patients
with CAD.9 A study by Elizari et al. concluded
that one of the most common causes of hemiblock
is CAD, and that the presence of left posterior
hemiblock, especially when associated with right
bundle branch block, predicts a great propensity
to develop complete AV block, even in the absence
of symptoms.10 Finzi et al. demonstrated that
nuclear myocardial perfusion imaging provided
noninvasive evidence that transient ischemia in
the territory of the posteroseptal segment of
the RCA may result in paroxysmal AV block
in patients with chronic infranodal conduction
abnormalities, regardless of the symptomatic
status.11
Advanced degrees of AV block are an
infrequent complication of Prinzmetal’s angina. A
study performed by Kerin et al. suggested that the
type and occurrence of a specific arrhythmia did
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not help predict the presence of CAD in patients
with variant angina. Furthermore, although the
authors reported a low incidence of advanced
AV block (3/26 – 11.5%), those with ST segment
elevation limited to the diaphragmatic leads
(implicating the right coronary artery) were appar-
ently at increased risk of high-degree AV block.12
Nevertheless, advanced conduction abnormalities
are not usually the form of presentation of variant
angina.
Despite these considerations, most studies
have shown that myocardial revascularization
does not result in any sustained improvement
in AV conduction. Patients who have severe
conduction disturbances and significant CAD may
well receive a pacemaker before revascularization
procedures13,14 [this does not apply to acute
coronary syndromes].
Following pacemaker implantation, the di-
agnosis of CAD through exercise stress testing
may not be possible. Studies have shown that
dobutamine stress echocardiography reduces con-
siderably the level of false-positive results in
these patients and still retain sensitivity for CAD
equal to that of exercise thallium-201 myocardial
computed tomography.15
In conclusion, a clear association between
CAD and AV nodal conduction abnormalities has
been unequivocally demonstrated, in spite of the
absence of sustained AV conduction improvement
following myocardial revascularization. Neverthe-
less, exclusion of CAD is mandatory in patients
with cardiovascular risk factors presenting with
spontaneous or exercise testing-induced complete
heart block. In case a pacemaker has been already
implanted, dobutamine stress echocardiography is
strongly supported by current literature.15
Degenerative Diseases
Degenerative abnormalities in the AV node
are the most frequent etiology of complete heart
block in elderly patients. Fibrosis and sclerosis
of the conduction system accounts for about one-
half of cases of AV block and may be induced
by several different conditions which often
cannot be clinically distinguished.16 However, the
prevalence/incidence of complete degenerative
AV block in young or middle-aged individuals is
unknown. Bilateral bundle branch scleroatrophy
and degeneration (particularly of the middle and
distal portions) and upper interventricular septum
crest fibrosis are typical histopathological findings
of the Lenegre disease,17 an idiopathic, fibrotic,
degenerative disease restricted to the His-Purkinje
system and not associated with inflammatory or
ischemic involvement of adjacent myocardium.
Lenegre’s disease has not been the target of
significant investigation in the last decades and
2012 3
 BARRA, ET AL.
case reports of Lenegre’s disease in youth have
been scarce.18 Histological studies have shown
that diffuse fibrotic degeneration of the whole
intraventricular cardiac conduction system exists
(differentiating this condition from the typical
channelopathies), which leads to AV block
without involvement of the sinus node and cardiac
fibrous skeleton. Some authors have suggested that
hereditary Lenegre disease is caused by a mutation
in the SCN5A gene, which in combination with
aging leads to progressive alteration in conduction
velocity.19 In fact, the SCN5A gene encoding the
human cardiac sodium channel alpha subunit
plays a key role in cardiac electrophysiology.
Mutations in SCN5A lead to a large spectrum of
phenotypes, including long-QT syndrome, Bru-
gada syndrome, and isolated progressive cardiac
conduction defect (Lenegre disease). Kyndt et
al. identified a G-to-T mutation at position 4372
by direct sequencing, which was predicted to
change a glycine for an arginine (G1406R) between
the DIII-S5 and DIII-S6 domain of the sodium
channel protein. This same mutation could lead
either to Brugada syndrome or to an isolated
cardiac conduction defect.20 The most common
phenotype of gene carriers of a Brugada syndrome-
type SCN5A mutation is progressive cardiac
conduction defects similar to the Lenegre disease
phenotype,21 which led some authors to suggest
the existence of an overlap syndrome between
these two syndromes22 and to recommend carriers
of a SCN5A mutation to be followed clinically
and electrocardiographically because of the risk
associated with severe conduction defects.21
Lev disease is manifested by bradycardia and
varying degrees of AV block due to noninherited
progressive degeneration and calcification of the
cardiac conduction system and fibrous skeleton
of the heart (mitral annulus, central fibrous body,
membranous septum, base of the aorta, and crest of
the ventricular septum). Lev disease has an onset
about the fourth or fifth decade (later than Lenegre
disease), although significant symptomatology is
only seen later in life. Also, contrary to Lenegre
disease, it tends to affect the proximal bundle
branches.23,24
Mitochondrial myopathy such as Kearns-
Sayre syndrome (one of the more severe and
systemically involved variants) may present as
advanced AV or intra/interventricular block,
especially the former, although patients usually
show a plethora of signs like ptosis, progressive ex-
ternal ophthalmoplegia, pigmentary retinopathy,
cerebellar ataxia, proximal muscle weakness, and
deafness before the occurrence of complete heart
block. Nevertheless, distal conduction defects are
constant findings and are a dominant factor in the
prognosis of this condition.25,26
4 2012
The presence of advanced atrioventricular
or intra/interventricular conduction abnormalities
in a relatively young adult without structural
cardiac disease or history of myocarditis and with
low risk for coronary artery disease should raise
the suspicion for primary degenerative cardiac
conduction system disease, especially if this
phenotype is shared with other family members or
in case of family history of sudden cardiac death or
Brugada syndrome. If a mitochondrial myopathy
is suspected, the patient should be examined by a
neuro-ophthalmologist.
Usually, pacemaker implantation becomes
necessary during the course of both Lenegre and
Lev disease.
Nonischemic Cardiomyopathies
AV and inter/intraventricular conduction
abnormalities are common findings in patients
with dilated cardiomyopathy (DCM). Inherited
mutations cause approximately 35 percent of cases
of DCM and the most frequent DCM-associated
mutations have been reported in the lamin A/C
gene (LMAC).27 Cardiac disease of LMAC-mutated
patients is classically defined by conduction
system and rhythm disturbances occurring early
in the course of the disease (requiring early
pacemaker implantation), followed by dilated
cardiomyopathy and heart failure. In fact, the
LMAC gene mutations account for 33% of cases
of DCM with AV block, all familial autosomal
dominant.28 Van Tintelen et al. highlighted
the role of LMAC mutations in patients with
DCM and/or conduction disease referred to their
cardiogenetics outpatient clinic, encountering a
severe phenotype in p.N195K mutation carriers
and preferential cardiac conduction disease in
p.R225X carriers.29
Considering DCM patients with LMAC mu-
tations have a poor prognosis compared with
other DCM patients,30 genetic testing should
be considered in patients with DCM when
clinical predictors of LMAC mutations are
present (presence of skeletal muscle involvement,
supraventricular arrhythmia, conduction defects,
and mildly dilated ventricles were predictors of
LMNA mutations in a study by Taylor et al.30 ),
regardless of family history. Also, because of high
clinical variability, LMAC mutation screening
should be considered in patients with familial lone
conduction disease.31
Mutations in the LMAC gene could also mimic
arrhythmogenic right ventricular cardiomyopathy
(ARVC) and some authors suggest LMAC gene
should be added to desmosomal genes when
genetically testing patients with suspected ARVC,
particularly when there is ECG evidence for
conduction disease.32
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 ATRIOVENTRICULAR BLOCK IN YOUNG ADULTS
Infectious Causes
High-degree heart block is an uncommon but
nonnegligible manifestation of acute myocarditis
in adults and may be the first manifestation
of the condition. Of the 3055 adult patients
with suspected acute or chronic myocarditis who
were screened in the European Study of the
Epidemiology and Treatment of Inflammatory
Heart Disease, 18% had high-grade arrhythmias
including ventricular arrhythmias or complete
heart block.33 In a different study, the rate
of advanced symptomatic heart block requiring
pacemaker implantation in biopsy-proven acute
lymphocytic myocarditis has been reported in up
to 8.3% of cases.34 A higher prevalence can be
observed in giant cell myocarditis, an uncommon
and idiopathic disorder in which up to 25% of
patients require pacemaker due to symptomatic
second- or third-degree heart block.35 Uemara et al
studied 50 patients with second- or third-degree
AV block (in whom the cause was not clear)
through endomyocardial biopsy (EMB) performed
from the right ventricle and concluded a high
number of lymphocytes per 400-fold magnified
field was a common finding and myocardial
lesions compatible with myocarditis could be
found in 6% of patients.36 Batra et al identified
a total of 40 patients younger than 20 years of
age with biopsy-proven myocarditis and advanced
AV block, reporting the return of AV conduction
within 7 days in 27 patients (67%) and the need
of permanent pacing in 11 patients (28%) with
persistent AV block.37
Besides viruses, multiple agents have been
associated with infectious myocarditis with ad-
vanced AV conduction abnormalities, includ-
ing protozoa,38 rickettsia,39 and bacteria. Two
agents deserve special emphasis: Borrelia species
bacteria (Lyme disease) and Trypanosoma cruzi
(Chagas disease). The former is the most common
tick-borne disease in the Northern Hemisphere
caused by at least three species of bacteria
belonging to genus Borrelia: Borrelia burgdorferi
in the United States and Borrelia afzelii and
Borrelia garinii in Europe. Borrelia is transmitted
to humans by the bite of infected ticks belonging to
a few species of the genus Ixodes. Cardiovascular
manifestations of Lyme disease often occur within
21 days of exposure and include fluctuating
degrees of AV block even in the absence of
significant symptomatology. This disease rarely
requires permanent cardiac pacing, as it is usually
self-limiting when treated appropriately with an-
tibiotics,40 but some reports have shown that Lyme
carditis can cause long-standing or irreversible
AV conduction defects despite adequate and early
antimicrobial therapy.41 Patients in an endemic
area presenting with cardiac symptoms should
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have a screening electrocardiogram along with
Lyme titers.
Chagas disease is a chronic parasitosis caused
by Trypanosoma cruzi infection affecting most
Latin American countries and presenting as a
late-developing chronic myocarditis or, much less
frequently, an early acute myocarditis. It is the
main cause of bundle branch block and AV
block in endemic areas and the leading cause of
cardiovascular death, mostly as a consequence of
heart failure and sudden death (due to malignant
ventricular arrhythmias or complete heart block)
in areas where the disease is endemic.42
Although EMB has long been the gold stan-
dard for confirming the diagnosis of myocarditis,
preliminary studies have shown that cardiac
magnetic resonance imaging (MRI) has become
an important tool for noninvasive assessment
of patients with suspected acute or chronic
myocarditis.43,44 Cardiac MRI can evaluate three
markers of tissue injury, namely intracellular
and interstitial edema, hyperemia and capillary
leakage, necrosis, and fibrosis. Furthermore, a
recent consensus statement recommends that
EMB be reserved for patients who are likely to
have specific myocardial disorders with unique
prognoses and specific treatment recommenda-
tions,45 such as cardiac sarcoidosis and giant cell
myocarditis.
In conclusion, acute and chronic myocarditis
are among the most important causes of advanced
AV block in young and middle-aged patients,
irrespective of previous symptomatology. Acute
myocarditis has been shown to be the cause of
sudden death, either by malignant ventricular
arrhythmias or complete heart block, in up to
12% of cases in autopsy studies of patients
less than 40 years of age, military recruits,
and young athletes.46 As this condition may
present as advanced AV block without previous
symptomatology, cardiologists should be aware
of this potential diagnosis in otherwise healthy
young or middle-aged adults at low coronary risk.
Rheumatic or Autoimmune Diseases
Several rheumatic or autoimmune diseases
have been associated to advanced AV conduction
abnormalities. In most conditions, the occurrence
of AV block is preceded by a multitude of signs or
symptoms, but, in some circumstances, complete
heart block may be the first manifestation of the
disease.
Giant-cell myocarditis (GCM) is a rare but
devastating disease (rate of death or transplan-
tation approximately 70% at 1 year following
diagnosis) that usually affects young, otherwise
healthy individuals and often associates with
thymoma, inflammatory bowel disease, and a
2012 5
 BARRA, ET AL.
variety of autoimmune disorders.47 It shares some
clinical and histological characteristics with car-
diac sarcoidosis but usually runs a more aggressive
course, typically presenting as rapidly progressing
heart failure, ventricular tachyarrhythmias, and
advanced conduction abnormalities. The latter
may the first sign of the disease. Kandolin et al.
evaluated 72 patients aged 18–55 years who un-
derwent pacemaker implantation for unexplained
third-degree AV block and found that 6% of
patients had biopsy-verified GCM. This diagnosis
associated with worse prognosis in a 4-year follow-
up (39% experienced either cardiac death, cardiac
transplantation, ventricular fibrillation, or treated
sustained ventricular tachycardia).48 Davidoff
et al. reported that ventricular tachycardia and
AV block requiring pacemaker implantation were
considerably more common in patients with GCM
compared with lymphocytic myocarditis (90% vs
25% and 60% vs 8.3%, respectively).34 EMB is
more sensitive in detecting GCM than cardiac
sarcoidosis because of the more widespread
myocardial inflammation in the former and should
be strongly encouraged in all adults aged less
than 55 presenting with unexplained high-degree
AV block. The importance of this diagnosis is
highlighted by the fact that treatment is consid-
erably different (involving immunosuppression)
than in infectious myocarditis and, rarely, a slower
progression or even self-limiting course may be
achieved.49,50
AV block may be a consequence of systemic
lupus erythematosus (SLE) as well, and few cases
of complete AV block as first manifestation of
adult lupus have been previously described.51
Although sinus tachycardia, atrial fibrillation,
and atrial ectopic beats are the major cardiac
arrhythmias in SLE, this condition may evolve
with AV conduction abnormalities and even
present as advanced AV block.52 Follow-up with
periodical ECG is recommended for adult lupus
patients to screen for possible conduction system
involvement, and treatment should be started
as soon as possible. Also, the diagnosis of SLE
should be suspected in young women presenting
with atrial arrhythmias and variable AV block,
regardless of symptoms.
AV conduction abnormalities may present
in different autoimmune conditions such as
rheumatoid arthritis and systemic sclerosis. In
the former, infiltration of the AV node can cause
right bundle branch block in 35% of patients
and, although AV block is rare, when it occurs
it is usually complete. In systemic sclerosis,
conduction disturbances occur in 25–75% of
patients and are due to fibrosis of the sinoatrial
and AV nodes, presenting as bundle and fascicular
blocks or variable AV block.52
6 2012
A genetic predisposition associated with HLA
B27 for developing complete heart block with or
without clinical or radiological signs of associated
rheumatic disease has been previously found. In a
series of 12 patients with spontaneous complete
heart block and HLA B27 associated disease
(of whom eight had ankylosing spondylitis)
undergoing electrophysiological study, 10 had
suprahisian second- or third-degree AV block
(eight spontaneously and two during atrial pac-
ing at rates below 90 impulses/min) and one
infrahisian block. In HLA B27-associated disease
the AV block seems to be preferentially located in
the AV node (with a predominantly suprahisian
location), although the conduction system may be
widely affected.53
Infiltrative Processes
Cardiac sarcoidosis (CS) is a granulomatous
inflammatory myocarditis with AV block as the
most common clinical manifestation along with
ventricular arrhythmias and heart failure.54 Diag-
nosis of CS is based on EMB results, which demon-
strate granulomatous inflammation/infiltration,
or, alternatively, on histologically confirmed extra
cardiac sarcoidosis combined with cardiac imag-
ing indicative of myocardial involvement.55 The
diagnosis of isolated CS is particularly difficult
because its confirmation depends solely on EMB,
the sensitivity of which is notoriously limited.
Although CS commonly results in AV block, it is
a rare disease, and the proportion it constitutes
of the total etiologic spectrum of AVB is not
well known. An earlier Japanese study found a
prevalence of 11.2% for clinically or histologically
diagnosed CS among consecutive patients aged
69 ± 13 years with high-degree AVB.56 Kandolin
et al. diagnosed cardiac sarcoidosis in 19% of
72 patients aged 18–55 years who underwent
pacemaker implantation for unexplained third-
degree AV block.48 In this series, 39% of
patients with AV block due to CS or GCM
had a major adverse cardiac event over a 2-
year follow-up. Similarly, Ardehali et al recently
showed that in patients with initially unexplained
dilated cardiomyopathy, EMB-verified sarcoidosis
portends a particularly poor outlook.57 Some data
suggest that corticosteroid therapy may improve
left ventricular function in CS and occasionally
correct the AV block, although it has no effect
on ventricular arrhythmias, which are probably
related to fibrotic areas promoting reentry and not
to myocardial edema and active inflammation.58
We emphasize the need for an exhaustive
assessment in young adults with unexplained
advanced AV block. The cardiac localization
disclosing sarcoidosis and the potential complete
AV block disappearance under therapy in this
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 ATRIOVENTRICULAR BLOCK IN YOUNG ADULTS
particular condition reinforce that observation.
Baseline ECG is the starting point, as abnormalities
on ECG (conduction disturbances, arrhythmias,
or nonspecific ST and T-wave changes) can be
demonstrated in 20–31% of sarcoid patients59 and,
although the relatively low sensitivity of resting
ECG for detecting cardiac involvement in patients
with sarcoidosis has raised some concerns, the
prevalence of ECG abnormalities correlates with
the severity of cardiac involvement. Cardiac
MRI and EMB should be performed on selected
cases.
Restrictive cardiomyopathy is the main find-
ing in cardiac amyloidosis, resulting from the
replacement of normal myocardial contractile
elements by infiltration and interstitial deposits
of amyloid. This process may also involve the
cardiac conduction system and cause different
types of heart block and arrhythmias. Electrophys-
iologic abnormalities were detected in 25 patients
with biopsy-proven AL amyloidosis in the form
of abnormal infra-His conduction times; infra-His
conduction time prolongation was shown to be an
independent predictor of sudden cardiac death.60
Fibrosis of the sinoatrial and atrioventricular
nodes has been correlated with the severity
of amyloid deposition elsewhere in the heart
and may require pacemaker placement. Cardiac
involvement is most common in immunoglobulin
amyloidosis, with specific avidity of certain
variable genes of the clonal B lymphocyte cells,
especially variable (V) lambda II light chain, to
cardiac tissues.61 About 50% of patients experi-
ence some cardiac manifestation related to their
disease, and at least 25% have congestive heart
failure.62 Although cardiac involvement is not as
common in familial amyloidosis as in the AL
type, and the prognosis is more favorable, patients
with the Met 30 transthyretin mutation may have
only conduction-system abnormalities and often
require pacemaker implantation.63 Despite these
considerations, Ridolfi et al studied the conduc-
tion system of 23 autopsy patients with cardiac
amyloidosis and abnormalities of conduction or
rhythm during life and suggested that, although
fibrosis of the cardiac conduction system was com-
mon, direct amyloid infiltration of the specialized
conduction tissue of the heart does not appear to
account for the majority of these disturbances.64
The discrepant anatomical and clinical evidence
highlights the need for accurate ECG controls in
all patients with confirmed or suspected cardiac
amyloidosis.65
Several case reports have demonstrated the
possibility of the occurrence of severe cardiac ab-
normalities (including advanced AV block or ma-
lignant ventricular arrhythmias) or even sudden
death as a consequence of cardiac amyloidosis,
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even in the absence of prior symptoms of heart
disease.66 Therefore, cardiac amyloidosis should
be suspected in patients presenting with AV
block and with echocardiographic abnormalities
compatible with restrictive cardiomyopathy, espe-
cially if the baseline ECG unveils generalized low
voltage. This diagnosis should not be neglected
in asymptomatic patients, as complete heart block
may be the form of presentation. If the combined
clinical and echocardiographic picture suggests
amyloidosis, then immunocharacterization of the
underlying amyloid protein can be obtained less
invasively from extracardiac tissue sites. However,
endomyocardial biopsy remains the definitive
diagnostic method for cardiac amyloidosis.67
Unfortunately, cardiac involvement generally de-
notes a poor prognosis, regardless of the method
of treatment. Syncope indicates a poor prognosis
as well, and is often a precursor of sudden cardiac
death.68
Metastatic involvement of the heart is an
uncommon phenomenon in clinical practice.
However, in rare circumstances, AV conduction
abnormalities may be the first sign of primary
occult neoplastic processes, as demonstrated for
occult lung cancer,69 non-Hodgkin lymphoma,70
primary cardiac lymphoma,71,72 cardiac heman-
gioma73 or mesothelioma of the AV node.74 Metas-
tases to the heart are relatively rare but should
be suspected if a patient with a known neoplasm
presents with new cardiac manifestations. In
most cases, however, AV block is not the first
manifestation.
Vagally Induced Atrioventricular Block
When transient AV block is recorded dur-
ing prolonged ECG recordings, distinguishing
between degenerative AV block and functional,
vagally induced AV block due to neurocardiogenic
reaction has important prognostic and therapeutic
implications. AV block during neurocardiogenic
reflex is rare, although it has been documented
during vasovagal and situational syncope.75,76 AV
block provoked by tilt test represents the cardioin-
hibitory component of the neurocardiogenic reflex
which is less frequent than sinus arrest, sinoatrial
block, or sinus bradycardia (vagal stimulation
on sinoatrial node usually predominates). Zysko
et al. reported an incidence of 5.2% of complete
AV block in patients with positive tilt test,77
similar to what had been previously found.78
Sinus rhythm slowing or irregular sinus rhythm
observed during (and sometimes preceding) the
AV block due to neurocardiogenic reflex indicate
its vagal origin. In fact, the association of sinus
bradycardia and AV block at the same time
strongly suggests vagal reflex as the mechanism
responsible and the increase in sinus rate or
2012 7
 BARRA, ET AL.

Table III.
Potential Diagnostic/Etiologic Algorithm for Otherwise Healthy Young or Middle-Aged Adult Patients with Advanced AV
Conduction Abnormalities

Advanced AV block in otherwise healthy young or middle-aged adult patient

↓
Baseline electrocardiogram, transthoracic echocardiogram, exercise stress testing, Holter, blood tests with thyroid
function and autoimmune panel

↓
Cardiovascular profile, symptoms, and/or Yes → Coronary artery disease screening with
exercise stress test suggestive of coronary coronariography or cardiac CT
artery disease?
No
↓
History of myocarditis or sarcoidosis? Family Yes → Cardiac MRI + endomyocardial biopsy if cardiac
history of infiltrative diseases? Heart failure sarcoidosis, giant-cell myocarditis, or
starting soon after AV block diagnosis? amyloidosis suspected
No
↓
Symptoms or autoimmune panel suggestive of Yes → Treat autoimmune condition. Referral to
autoimmune disease? autoimmune disease center or expert.
No
↓
AV block preceded by sinus rate decrease or Yes → Tilt table test
sinus arrhythmia?
No
↓
Family history of dilated cardiomyopathy, lone Yes → Lamin A/C and SCN5A genetic testing
severe conduction disturbances, or Brugada
syndrome?
No
↓
Degenerative idiopathic AV block likely

This algorithm is solely for diagnostic purposes. Decision to implant a pacemaker must accord to existing guidelines. In Latin American
countries, the possibility of Chagas disease must be considered.

lack of decrease during the episode of the AV by sinus rhythm slowing and/or PR interval
block argues against underlying neurocardiogenic prolongation.
reflex.79,80 Also, vagally induced AV conduction
disturbances have a gradual rather than abrupt Rare Causes For Complete Atrioventricular
emergence. Block
It is possible that endogenous adenosine In very unusual circumstances, some condi-
plays an important role as a modulator of tions may present as advanced or complete AV
syncope or even asymptomatic sino-atrial and AV block:
nodal conduction abnormalities induced during
tilt testing.81 High adenosine plasma levels and • Radiation-induced83
high expression of adenosine A2A receptors are • Psychiatric conditions84
observed in patients with unexplained syncope • Unexplained apoptosis of the cardiac
and positive head-up tilt test.82 conduction system85
In conclusion, vagally induced AV block • Acute rheumatic fever86
poses a challenging diagnostic dilemma. This • Left ventricular noncompaction87
should be considered when other potential • Neurologic disorders such as scapuloper-
diagnoses have been excluded and especially if oneal dystrophy and the oculocraniosomatic
the occurrence of AV block, either spontaneous syndrome88
or induced at tilt test termination, is preceded • Thyroid disorders89

8 2012 PACE, Vol. 00

 ATRIOVENTRICULAR BLOCK IN YOUNG ADULTS
Diagnostic Algorithm
Table III suggests a potential diagnos-
tic/etiologic algorithm for otherwise healthy
young or middle-aged adult patients with ad-
vanced AV conduction abnormalities. It covers the
most prevalent causes of AV block in this specific
group, namely coronary artery disease, myocardi-
tis, cardiac sarcoidosis, giant cell myocarditis,
cardiac amyloidosis, autoimmune conditions such
as systemic lupus erythematosus or rheumatoid
arthritis, vagally induced AV block, lamin A/C
mutation, Lenegre disease, and degenerative
idiopathic AV block. Chagas and Lyme diseases
were not considered in the development of such
an algorithm, but their importance should not be
neglected in endemic areas. This is particularly
true in Latin American countries, considering the
high prevalence of human Chagasic disease.
Limitations of the Review
Considering the rarity of advanced AV block
in young or middle-aged adults and the scarcity of
publications about this subject, current scientific
evidence is sometimes found in case reports rather
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