Maria Penco, Ernesto Di Cesare*,
Giuseppe Aurigemma**, Antonella Costanzi*, Francesco Marchese*, Alessia Catalucci*,
Francesco Fedele**, Carlo Masciocchi*.
Cardiology, Department of Internal Medicine, University of L'Aquila,
*Department of Radiology, University of L'Aquila, **Cardiology, Department of
Cardiovascular and Respiratory Sciences, University "La Sapienza" of Rome, Italy
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The original description of the so-called
arrhythmogenic right ventricular dysplasia (ARVD) was by Dalla Volta et al in 1961, with
the term ARVD coined by Frank et al in 19781,2.
In the 1995 report of the World Health Organization/International Society and
Federation of Cardiology, Task Force on the Definition and Classification of
Cardiomyopathies, this disease was classified as arrhythmogenic right ventricular
cardiomyopathy3.
Arrhythmogenic right ventricular cardiomyopathy is characterized by progressive
fibrofatty replacement of right ventricular myocardium, initially with typical regional
and later global right and some left ventricular involvement, with relative sparing of the
septum4. Familial disease is common, with autosomal
dominant inheritance and incomplete penetrance; a recessive form is described.
Presentation with arrhythmias and sudden death is common, particularly in the young5.
Although several theories have been advanced, the aetiology and pathogenesis of ARVD
remain unknown. In the dysontogenetic theory, the absence of myocardium is considered the
consequence of a congenital aplasia or hypoplasia of the right ventricular wall, leading
to a parchmentlike appearance2,6. The use of the term
"dysplasia" (which means "maldevelopment") is in agreement with this
view.
In the degenerative theory, the loss of myocardium is considered a consequence of
progressive myocyte death due to some metabolic or ultrastructural defects. Familial
occurrence suggests a genetic disease with autosomal dominant transmission and variable
expression and penetrance. The finding of a gene defect localized in the chromosome
14q23-q24, which includes the beta-spectrin and alfa-actinin genes, the mutation of which
might be involved, is in agreement with this view7-10.
In the inflammatory theory, the fibrofatty replacement is viewed as a healing process
in the setting of chronic myocarditis11-13. An
infectious and/or immune myocardial reaction might intervene in the etiology and
pathogenesis of the disease. This is not in contrast with a familial occurrence because a
genetic predisposition to viral infection eliciting immune reactions cannot be excluded.
Regional sympathetic dysinnervation was recently demonstrated with the use of
myocardial scintigraphy. Whether this corresponds to an amine depletion or a true nerve
disruption remains to be established14.
Results of pathological studies clearly demonstrate that ARVD is a primary heart
muscle disorder (cardiomyopathy) characterized by a progressive loss of myocardium, with a
peculiar fatty or fibrofatty replacement, that accounts for the onset of cardiac
electrical instability. The acquired nature of disease (possibly postnatal phenotype
expression) is corroborated by the age range of the affected patients (15 to 65 years),
the nearly preserved distance of the epicardium from the endocardium without apposition of
the two layers, and, most important, the observation of patchy myocyte death associated
with inflammatory infiltrates and fibrofatty repair in various stages of healing. Whether
the inflammation is a primary event or secondary to the spontaneous cell death remains an
intriguing question. Furthermore, whether the fatty variety of ARVD actually represents a
completely different entity remains to be determined15,16.
It has recently been hypothesized that myocardial cell death in ARVD might represent a
programmed death ("cell suicide") known as apoptosis, triggered by different
viruses in the absence of an inflammatory response, and contribute to the loss of
myocardial cells in this disorder17-19.
There are several reports of concomitant minor abnormalities of the left ventricle in
ARVD. Although right ventricular abnormalities are predominant, it is not unusual to find
abnormalities in the left ventricle. These may be present at the time of the diagnosis, or
may become apparent or progress during the course of the disease. The left ventricle is
usually not dilated but may show segmental as well as diffuse wall motion abnormalities12,16,20,21. Even more, left ventricular lesions
associated with ARVD are predictable by QRS abnormalities22.
There is a wide spectrum of clinical presentation and findings on physical examination
due to the polymorphism of this condition, and different extension of the pathologic
process (extensive, moderate, mild). For this reason, it is quite difficult to diagnose
the minor forms of the disease, which are usually characterized by cryptogenetic,
apparently idiopathic, often asymptomatic, ventricular arrhythmias. The majority of
patients are aged between 7 and 40 years with a slight male preponderance. The most common
presentation is that of a young healthy adult with malaise or palpitations during
exercise. Exercise-related ventricular tachycardia is not an infrequent presentation.
Patients may also complain of easy fatigue, effort-syncope or even present with sudden
death23-28.
Properly, in a recent report, a task force of European Society of Cardiology proposed
some useful criteria for diagnosis of ARVD, classified as major or minor as a function of
criteria's specificity, and based on the identification of structural abnormalities, fatty
or fibrofatty replacement of the right ventricular myocardium, electrocardiographic
changes, right ventricular arrhythmias, and familial disease4.
The most common finding on the electrocardiogram is T-wave inversion in the anterior
precordial leads, usually limited to V1-V3. Ventricular arrhythmias are also frequent,
from isolated ventricular extrasystoles to episodes of ventricular tachycardia, usually of
the left bundle branch block morphology. Delayed potentials on surface ECG are reported,
but their detection usually requires a high resolution ECG or signal-averaging techniques.
The properties of late potentials may also change with time in ARVD patients and follow-up
by repeated signal-averaged ECG does not appear to be useful in predicting the
susceptibility to ventricular tachycardia in ARVD29-31.
The study of the families in which this disease is present showed that among the
affected family members 50% were asymptomatic, 45-38% presented late ventricular
potentials and/or ECG abnormalities, mainly not severe forms, and only 5% suddenly died28,32.
Several reports have suggested that echocardiography can identify right ventricular
morphological and functional abnormalities associated with ARVD33-35.
Features suggestive of ARVD include diastolic bulge of the right ventricle, systolic
dyskinesia of the inferobasal wall, disarray of trabecular pattern, structural
abnormalities of the moderator band, right ventricular dilation with or without
generalized dynamic impairment, and apical dyskinesia. Doppler evaluation commonly
demonstrates the altered diastolic properties of the right ventricle with a significant
decrease in E/A velocity ratio. Nevertheless, noninvasive identification may be difficult
because of technical limitations in imaging right ventricular structure. Even more, this
technique is subjective, depends on the operator's experience and does currently not
provide information on tissue composition. Echocardiography remains a sensitive but
non-specific detector of right ventricular morphological and functional abnormalities, and
interpretation of the echocardiographic findings should therefore be in the clinical
context of the case.
Right ventricular angiography is currently regarded as the standard for the clinical
diagnosis of ARVD. The most specific angiographic features of ARVD are morphological and
motion abnormalities localized to the free wall, particularly bulges and mamillated
akinetic areas. The positive predictive value of an RV angiogram is in excess of 80%, with
a negative predictive value of approximately 95%36-39.
The more specific diagnosis of ARVD can be made when additional evidence of abnormal
fibrolipomatous infiltration of the right ventricular myocardium is present or when
endomyocardial biopsy is performed. Nevertheless, endomyo-cardial biopsy, although very
specific, is not sensitive, as the syndrome rarely involves the septum, which is the only
region of the right ventricle that can be sampled safely by biopsy40.
In fact, typical locations of fatty or fibrous replacement are the right ventricular apex,
outflow tract, and the inferior subtricuspid wall, known as the triangle of dysplasia.
Ventricular endomyocardial biopsy can prove useful in confirming the diagnosis of ARVD, as
recommended by the European Society of Cardiology, but a negative biopsy does not exclude
ARVD, particularly if clinical and angiographic evidence is present.
Even more, because repeated follow-up examinations are necessary and the patients are
usually young, a noninvasive method of assessing abnormal findings in ARVD patients is
desirable41.
There have been few studies of programmed electrical stimulation in ARVD. They were
only able to induce sustained ventricular tachycardia in subjects with spontaneous
ventricular tachycardia. Therefore, these studies are unlikely to help in risk
stratification42.
Magnetic resonance imaging (MRI) is capable of distinguish the myocardium from the
surrounding structures, such as fat and blood, and therefore might be particularly suited
to visualize the complex right ventricular architecture. In addition to morphologic
characterization of spin-echo images, cine-MR imaging allows quantification of ventricular
function43-54.
The essence of ARVD diagnosis by MRI depends on the visualization of fat or evidence
of right ventricular dilation or extreme thinning in the infundibulum and the inferior or
diaphragmatic free wall of the right ventricle. Importantly, the site of fatty replacement
of the myocardium does appear to correspond to the region from which the tachycardia
arises. Cine-MR can also be used to define dilation of the right ventricle and localized
dyskinetic regions of the myocardium. The noninvasive nature of MRI makes it an excellent
screening tool for the detection of the disease and a worthy substitute for invasive
procedures in the follow-up of ARVD patients.
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