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From the Department of Cardiology, Hôpital Jean Rostand, Ivry sur
Seine, France.
Correspondence to Guy Fontaine, MD, PhD, Department of Cardiology, Hôpital Jean Rostand, 39 rue Jean Le Galleu, 94200 Ivry sur Seine, France.
In this issue
of Circulation, Burke et al1 report
the results of a morphological and morphometric analysis of RV
myocardium to differentiate fatty infiltration of the RV
free wall from fibrofatty infiltration, which is the
histological marker of ARVC. A similar analysis
was previously presented by Thiene et
al,2 classifying their patients as having
"lipomatous" as opposed to "fibrolipomatous" replacement of the
myocardium and putting the two entities in the same group.
Unless small areas of fibrosis are overlooked, the two subgroups of
Burke et al and Thiene et al have the histological
picture of myocardium intermingled with and/or replaced by
fat without associated fibrosis. In this population of patients who
died suddenly, we are faced with the observation that strands of
myocardial fibers within fat without fibrosis may lead to sudden death.
This possibility has rather important consequences, because a large
proportion of seemingly normal hearts have fatty infiltration of the RV
myocardium.3 It may be that the fatty
pattern in these patients represents the early stage of the
disease before the appearance of fibrotic tissue. Therefore, a large
proportion of normal individuals may in fact have the prerequisite for
the development of RV cardiomyopathies.
It is well known that a large majority of patients with ARVD have
histological evidence suggestive of inflammation. It
may be that if myocarditis is superimposed on the background of
myocardium interspersed by fat, strands of
cardiomyocytes involved in myocarditis will produce
fibrosis and will transform the purely fatty to the fibrofatty form.
Activation of neutrophils induced by myocarditis will enhance the risk
of arrhythmogenesis.4 Therefore, the two groups
identified by Burke et al may represent two consecutive stages
of myocardial disease progression.
It is possible that multiple attacks of myocarditis could lead to
the destruction of an increasing number of myocardial cells involving
both the right and the left ventricles, causing irreversible heart
failure that is similar to the pathological findings of end-stage
dilated cardiomyopathies.5 If
the additional factor of an abnormal host immune response is involved,
this could lead to an autoimmune phenomenon, accelerating myocardial
dysfunction. Therefore, the new group of
cardiomyopathies recently introduced in the WHO
classification encompasses a wide spectrum of diseases that have the
same basic histological structure but may have
different clinical presentations and
outcomes.6 On the basis of these concepts as well
as the probable mechanism of adipogenesis, we propose a classification
of ARVCs based on our current experience of >250 patients and 72
histological samples collected during a period of 23
years in France and 7 other countries, including the United States,
Japan, and Australia.7
Isolated RV Dysplasia
Pure Form of ARVD
The typical histological pattern of ARVD consists of
replacement of midmural and/or external layers of RV
myocardium (and to a much lesser extent, LV
myocardium) by fatty tissue and fibrosis bordering or
embedding strands or sheets of cardiomyocytes. Thickening
of the media of distal coronary vessels, which may explain
atypical chest pain observed in these patients, is another marker of
the disease (syndrome X?).
ARVD appears to be the result of a genetically determined abnormality
of development observed early in life, possibly even in the embryo, as
the possible result of a mutation in the dHAND transcription factor,
mostly controlling RV development.9 We have
observed infiltration of myocardium by fat without fibrosis
or inflammatory signs in a 27-week-old fetus that was brought to our
attention because of RV aneurysm and arrhythmias
observed in utero (Figure
Because of minor involvement of the left ventricle, LV failure is not
observed. In some cases, RV failure could be the result of severe
progression of the original dysplastic phenomenon in the right
ventricle.
Naxos Disease
Venetian Cardiomyopathy
Noncoronary RV Precordial ST-Segment Elevation
RV Outflow Tract Tachycardia
Benign Extrasystoles
Uhl's Anomaly
It has been suggested recently that Uhl's anomaly and ARVD share
a similar pathogenesis. Uhl's anomaly appears to be the result of an
extensive and complete apoptotic destruction of RV
myocardium as opposed to ARVD that may be due to a
localized transient phenomenon progressing over a long period of
time.25
Mitral Valve Prolapse
Nonarrhythmogenic Forms of ARVD
Dysplasia With Major LV Involvement
Biventricular Dysplasia
Dysplasia Complicated by Myocarditis
The term "myocarditis" is used to indicate a
histological picture consistent with acute
inflammation. This inflammatory process may be the result of multiple
causes (viral, bacterial, fungal, toxic, autoimmune, etc), it may be
localized or diffuse, and it may be observed at different stages of
evolution. It may also be associated with a wide spectrum of clinical
manifestations ranging from absence of symptoms and complete resolution
to death within a few days.31
It is commonly accepted that patients with structural heart disease are
more sensitive than normal individuals to myocarditis, and the two
recent analyses of sudden death in athletes in whom myocarditis
has been identified strongly supports this
hypothesis.32 33
When myocarditis involves both ventricles, congestive heart failure can
cause death in an additional 1% of patients per year. At a late stage
of the disease, it is difficult to distinguish ARVD from an advanced
form of idiopathic dilated
cardiomyopathy.5
The diagnosis of ARVD is even more difficult in cases of myocarditis
complicating the nonarrhythmogenic form. Therefore, patients with RV
dysplasia could present with a clinical overt or concealed
myocarditis and a clinical evolution consistent with idiopathic
dilated cardiomyopathy. Microscopic
histological examination of the RV free wall will show
the pattern of dysplasia. However, this diagnosis could be obscured by
the signs of myocarditis and may escape attention if not specifically
looked for.34
We have reported one case of fulminant heart failure due to
catastrophic myocarditis superimposed on the background of typical ARVD
and another case of long-term evolution of LV dysfunction resulting in
death with a typical pattern of ARVD on the right side of the heart and
chronic progressing myocarditis on the
left.31 34
Differential Diagnosis
Idiopathic Dilated Cardiomyopathy
Isolated Myocarditis
Pure myocarditis could be by itself arrhythmogenic, both during
its acute phase and after its complete healing. This has recently been
confirmed in cases of sudden death during
sports.32 33
Adipomatosis Cordis or Cor Adiposum
Conclusions
Selected Abbreviations and Acronyms
Acknowledgments
This work was supported by the Gustave Prévot Foundation,
Geneva, Switzerland.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
© 1998 American Heart Association, Inc.
Editorials
Arrhythmogenic Right Ventricular Cardiomyopathies
Clinical Forms and Main Differential Diagnoses
Key Words: Editorials • cardiomyopathy • genetics • apoptosis • death, sudden
The macroscopic pattern of ARVD consists of dilatation of the
right ventricle with bulges located in the infundibular, apical, and
subtricuspid areas (the triangle of dysplasia). Most of the RV muscle
is replaced by fat.8 
). Few pediatric cases of ARVD
have been reported.10 11 After a phase of latency
in which only ECG signs may be present, the early clinical
manifestation is usually that of ventricular
arrhythmias originating in the right ventricle, observed during
adolescence and in early adulthood. In some cases, sudden death is the
first presenting symptom of the disease.2
With conventional unguided drug treatment, the incidence of sudden
death is 1% per year.
View larger version (71K):
[in a new window]
Figure 1. Evidence of right lateral aneurysm of a 27-week-old
fetal heart, arrhythmogenic in utero. Histology shows evidence of
adipocytes interspersed with myocardial fibers. Neither fibrosis nor
signs of inflammation were observed. Hematoxylin-phloxine-saffron
stain; magnification x400.
The Naxos disease is a form of ARVD, which has been observed
on the island of Naxos, Greece; it involves 25 patients from 12
families. It is an inherited condition with a recessive form of
transmission and a familial penetrance of 90%. It is associated with
another dysplasia, palmoplantar keratosis.12
Clinical signs, ECGs, and biopsies are consistent with
ARVD.13 Clustering of the disease on this island
may have resulted from inbreeding that occurred in the same manner as
that observed in south Suffolk with familial
cardiomegaly.14
Venetian cardiomyopathy (originally called RV
cardiomyopathy)2 has most of
the clinicopathological presentations of ARVD, but the
familial incidence reaches a level of 50% in the Veneto region, as
opposed to no more than 15% to 25% in other series. The degree of
familial penetrance is less than in Naxos disease. Of interest is that
the island of Naxos was occupied twice by Venetian merchants. Our case
of ARVD diagnosed in utero was from the Veneto region. The youngest
patient with ARVD who died suddenly at age 7 was of Italian descent.
There are also an increased number of sudden deaths in family members,
patients from three generations, and a larger number of patients with
LV involvement.15
This syndrome has been observed in young adults who have a risk of
sudden death during rest or sleep.16 Some
patients with the typical ECG findings of this condition have
ARVD.17 18 Sudden death during sleep observed in
young males with intermittent ST-segment elevation, reported in South
East Asia, may pertain to the same condition. However, no pathological
examination of the RV free wall is currently
available.19 However, some cases of Pokkuri
disease described in Japan are also histologically
proven examples of ARVD.20
RV outflow tract tachycardia patients studied by MRI
show signs of structural heart disease. This was confirmed in some
cases by contrast angiography, strongly suggesting the presence of ARVD
localized to the infundibular area.21 However,
other arrhythmogenic substrates have been suggested, but the prevalence
of ARVD cases in this group needs further
study.22
Benign extrasystoles have a pattern suggesting an
infundibular origin. Patients with outflow tract
ventricular tachycardia may have the same QRS
morphology. Therefore, it is not surprising that some patients who have
PVCs of this morphology may have ARVD. We recently observed a teenage
patient who had PVCs arising from the infundibulum. She was
resuscitated from cardiac arrest but finally died of irreversible brain
damage. The histological pattern of ARVD was associated
with an exceedingly large amount of interstitial fibrous
tissue in the infundibular area associated with inflammatory
reaction.23 We think, however, that the cause of
death was more probably related to myocarditis than a
histological pattern of dysplasia localized to the
infundibulum.
This extremely rare anomaly falls into two age groups and has a
clearly distinctive clinical as well as pathological
presentation. Uhl's anomaly generally leads to congestive
cardiac failure at an early age and death after few weeks or months. In
the adult age group, death is either the result of congestive heart
failure and/or cardiac arrhythmias. Uhl's anomaly shows the
striking and unmistakable pattern of a huge and transparent RV free
wall. This is the result of apposition of the endocardium with the
epicardium with some fatty tissue but without intervening
myocardium.24 In some cases, the
anomaly is limited to a small zone of the RV free wall and may be
discovered by chance at autopsy.
A systematic pathological study of sudden death patients
with clinically suspected or autopsy-discovered mitral valve prolapse
from the Veneto region of Italy showed that two thirds of these
patients had the RV histological substrate of
ARVD.26 This finding may explain the
inconsistencies in the results of surgical replacement of the mitral
valve for the prevention of arrhythmias and sudden death in
patients with mitral valve prolapse.27 However,
as with the Venetian cardiomyopathy, it is
necessary to consider the possibility of disease clustering in the area
of the world from which this report originates.
The new WHO classification has included the term
"arrhythmogenic" in ARVC. However, cardiac arrhythmias are
an epiphenomenon, and some patients with a clear-cut pattern of ARVD
discovered by invasive or noninvasive tests of the RV
myocardium do not have ventricular
arrhythmias. In those patients, the arrhythmogenic substrate is
present but silent. These patients may have ECG signs of ARVD and
late potentials detected by signal averaging. This could explain
false-positive results observed in some apparently normal
individuals.
Pure Biventricular Dysplasia
This form is characterized by the same disease process involving
the left as well as the right ventricle. The typical
histological structure is observed in the LV free wall,
which is replaced by fatty tissue, and there should be strands of
cardiomyocytes embedded in or bordered by fibrosis.
Biventricular dysplasia can lead to cardiac insufficiency
because of excessive loss of LV myocardial tissue and may be wrongly
diagnosed as idiopathic dilated
cardiomyopathy.28 However,
identification of infiltration of the left ventricle by fat should lead
to the correct diagnosis.
Dysplasia may also be complicated by a large amount of
inflammatory reaction in a small percentage of patients. In this case,
both ventricles are generally involved, and the prognosis is
poor.29 Because only a small number of patients
with ARVD have no inflammatory infiltrates, it may be deduced that
myocarditis is probably superimposed on the genetically determined
structural background of ARVD. A striking demonstration of this concept
is the study of identical twins with completely different evolution,
suggesting both familial and environmental
factors.30
Idiopathic dilated cardiomyopathy at an early
stage of the disease when there is still some preservation of LV
function with ventricular tachycardia
originating from the right ventricle may be mistaken for ARVD. However,
cardiac imaging will demonstrate global dilatation and hypokinesia of
both ventricles, as opposed to the segmental abnormalities that are a
typical feature of arrhythmogenic RV
dysplasia.35
The histological diagnosis in most of these cases
is unmistakable, but it could be confusing when myocarditis results in
a large number of adipocytes. However, the topographic distribution of
fat will not be similar to ARVD.
This form, discovered by chance at autopsy, looks like
biventricular dysplasia, with a continuous layer of fatty
tissue covering both ventricles.36 There are no
ventricular arrhythmias. However, the distinction
from ARVD is that this form typically has no fibers embedded in fat on
either the right or the left ventricle.
The polymorphism and wide clinical spectrum of ARVCs in
general appears to be the result of one and possibly two basic
characteristics of the heart musculature of the human species:
replacement of myocardium by fat and susceptibility to
environmental factors. These features could be a contributing factor in
many causes of death. Without properly assessed pathological data, it
is impossible to estimate their real significance in the population at
large. However, it is certain that ARVCs are much more frequent than
previously recognized. In addition, greater knowledge of ARVCs will
help to understand other cardiomyopathies.
Therefore, enrollment of cases in an international registry of patients
with ARVC could enhance the proper identification and understanding of
multiple diseases of the myocardium and will stimulate both
basic and clinical research. Registries for ARVC have now been
established both in the United States and in Europe.
ARVC
=
arrhythmogenic right ventricular cardiomyopathy
ARVD
=
arrhythmogenic right ventricular dysplasia
LV
=
left ventricular
PVC
=
premature ventricular contraction
RV
=
right ventricular
WHO
=
World Health Organization
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