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Arrhythmogenic Right Ventricular Cardiomyopathy 2012:
Diagnostic Challenges and Treatment
FRANK I. MARCUS, M.D. and AIDEN ABIDOV, M.D., Ph.D.
From the Section of Cardiology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona, USA
ARVC 2012. The most common presentation of arrhythmogenic right ventricular cardiomyopathy
(ARVC) is palpitations or ventricular tachycardia (VT) of left bundle branch morphology in a young or
middle-aged individual. The 12-lead electrocardiogram may be normal or have T-wave inversion beyond V 1
in an otherwise healthy person who is suspected of having ARVC. The most frequent imaging abnormalities
are an enlarged right ventricle, decrease in right ventricular (RV) function, and localized wall motion
abnormalities. Risk factors for implantable cardioverter defibrillator include a history of aborted sudden
death, syncope, young age, decreased left ventricular function, and marked decrease in RV function.
Recent results of treatment with epicardial ablation are encouraging. (J Cardiovasc Electrophysiol, Vol.
pp. 1-5)
arrhythmogenic right ventricular cardiomyopathy, implantable cardioverter defibrillator, RV dysplasia, sudden
death, ventricular tachycardia
Arrhythmogenic right ventricular cardiomyopathy
(ARVC) is an inherited cardiomyopathy characterized by the
predominance of ventricular arrhythmias.1 The presenting
clinical manifestations usually consist of palpitations
because of premature ventricular beats (PVCs), lightheadedness or syncope because of rapid monomorphic ventricular
tachycardia (VT) or uncommonly sudden death as a result of
ventricular fibrillation. Symptoms usually appear between
the ages of 30–50 but there is a wide range of the onset
of symptoms from age 10 to the 80s. Because ventricular
arrhythmias usually originate from the right ventricle, the
ventricular arrhythmias have left bundle branch morphology.
Therefore, suspicion for the diagnosis of ARVC is increased
when the ventricular arrhythmias have left bundle branch
block (LBBB) morphology and particularly when the QRS
axis is superior. This is exemplified by a positive QRS
complex in lead AVL indicating an origin from the body
of the right ventricle rather than from the right ventricular
(RV) outflow tract. Nevertheless, PVCs may arise from
the RV outflow tract in ARVC. If so, the diagnosis must
be differentiated from patients who have idiopathic VT
(RVOT).
Another interesting characteristic of these patients is that
their sustained VT may be quite rapid, in the range of
200–250 beats/minute, yet the patients may tolerate this for
many hours because the left ventricle has normal or nearly
Dr. Abidov reports research support from Phillips and Astellas Pharma Inc.
Dr. Marcus: No disclosures.
Address for correspondence: Frank I. Marcus, M.D., University
of Arizona Medical Center, Sarver Heart Center, 1501 N. Campbell Avenue, Tucson, AZ 85724-5037. Fax: 520-626-4333; E-mail:
[email protected]
Manuscript received 4 June 2012; Revised manuscript received 26 June
2012; Accepted for publication 03 July 2012.
doi: 10.1111/j.1540-8167.2012.02412.x
normal function. In patients who present with sustained
rapid VT of LBBB morphology the likelihood of ARVC is
greatly enhanced if during sinus rhythm the T-waves are inverted in the precordial leads especially in V 1 –V 3 or beyond
(Fig. 1).2 This finding is uncommon in patients who do not
have overt heart disease.3 A caveat regarding the specificity
of T-wave inversion in the anterior precordial leads is that Twave inversion in V 1 –V 4 was found in 12.7% of athletes of
black ethnicity.4 One clue to assist in differentiating these Twave inversions in healthy black athletes from patients with
ARVC is that most (64%) of T-wave inversion in the anterior
leads in black athletes were preceded by convex ST segment
elevation, an unusual finding in patients with anterior T-wave
inversion who have RV cardiomyopathy.4
Epsilon waves are low amplitude complexes after the end
of QRS complex in leads V 1 –V 3 (Fig. 1). They are uncommonly seen in newly diagnosed patients with ARVC, but are
a major diagnostic criterion.
The usual differential diagnosis in patients suspected of
ARVC who have PVCs or monomorphic VT arising from
the RVOT is that of idiopathic VT. It is important to differentiate these 2 conditions because they have markedly
different prognosis. RVOT tachycardia is not an inherited
cardiomyopathy. Therefore, family members do not need to
be concerned that it will be genetically transmitted. In addition, RVOT tachycardia rarely degenerates into ventricular
fibrillation. Therefore, sudden death is not a clinical feature
and ICD’s are not indicated for prevention of sudden cardiac
death in patients with RVOT tachycardia. The proper identification of these 2 conditions can usually be made clinically.
As mentioned previously, patients with RVOT tachycardia do
not have a family history of cardiomyopathy and T-wave inversion in V 1 –V 3 or beyond is present in only 4% of patients
with RVOT tachycardia but can been seen in 47% of newly
diagnosed patients with ARVC.5 The 12-lead ECG obtained
during VT can also assist in properly identifying the etiology
of the condition responsible for the RVOT tachycardia.6,7
A QRS duration of >120 milliseconds in lead 1 has a sensitivity of 88–100%, specificity of 46%, positive predictive
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Journal of Cardiovascular Electrophysiology
Vol. No.
Figure 1. ECG of a 42-year-old woman with ARVC. The T-waves are inverted in V 1 –V 5 . An epsilon wave is present (arrow) in leads V 1 and V 2 .
value of 61%, and a negative predictive value of 91–100% for
ARVC.6 The presence of QRS notching in any leads during
ventricular tachycardia favors the diagnosis of ARVC.7
Electrophysiological testing can assist in the diagnosis. If
VT can be induced with multiple LBBB morphologies arising
from both the RVOT with an inferior QRS axis as well as from
the body of the RV with a superior QRS axis, it greatly favors
the diagnosis of ARVC. If the diagnosis is established and if
there is a recording of the clinical VT, an electrophysiological
study may provide only limited information because there is
a strong relation between the cycle length of the clinical VT,
induced VT, and follow-up VT (R = 0.62–0.88).8
If an electrophysiological study is performed, additional
tests at the time of this procedure may provide useful diagnostic information. These include voltage mapping that can
reveal areas of low voltage because of endocardial scar in
ARVC that is not present in RVOT tachycardia. However,
the absence of low-voltage areas in the right ventricle does
not exclude ARVC particularly in the early stage of the disease. This is because the fatty-fibrous infiltrate starts in the
epicardium and proceeds to the endocardium.9 Areas of low
voltage may be considerably larger in the epicardium.10 If
low-voltage signals are present in the right ventricle this can
aid in localization of the area to perform endocardial biopsy;
specifically at the junction of the normal myocardium with
the affected areas because the disease may be spotty and a
random biopsy may miss the involved area.11,12 In addition,
it is well to avoid biopsy in the center of the ventricular scar
because that may be an area that is markedly thin and the
risk of perforation may be increased if biopsy is performed
in this region.13 Septal biopsies are not advisable because
the typical pathology of RV cardiomyopathy is not usually
present in the septum.14
An additional useful test that can be done in conjunction
with the electrophysiological study is that of a RV angiogram
performed in the 30◦ RAO and 60◦ LAO views. The pro-
tocol for performing this test is provided on the Web site
www.arvd.org. During contrast injection it is important to
avoid the catheter touching the RV endocardium to prevent
the initiation of premature ventricular complexes that can interfere with the interpretation of the angiographic findings.15
As previously mentioned, biopsy of the septum is unrevealing for the pathology of ARVC using standard pathological techniques. However, new findings suggest that biopsy of
the septum may assist in the diagnosis of ARVC if imunostaining reveals that plakoglobin is not localized to the gap
junctions, whereas it is localized to the gap junctions with
other cardiomyopathies (excluding giant cell myocarditis and
sarcoidosis).16
This discussion has focused on the diagnosis of typical
ARVC. However, the spectrum of this disease has been expanded because of the knowledge that similar genetic abnormalities can manifest as biventricular involvement or even
with a left ventricular (LV) dominant abnormality suggesting dilated cardiomyopathy.17 In the latter case, a causative
desmosomal abnormality is suggested by dominance of ventricular arrhythmias. The new Task Force Criteria have incorporated this finding, and considerable changes have been
made to assist the physician to accurately diagnose ARVC.18
The New Task Force Criteria may be found on the web
(www.arvd.org).
Because it is now well known that ARVC is a genetic cardiomyopathy, transmitted primarily as an autosomal dominant disease, the question arises as to the role of genetic testing, either for diagnosis, prognosis, or for identifying family
members who may have the disease and may not be symptomatic. The genetic abnormality is associated with structural
changes in the desmosomes. Desmosomes are proteins that
bind the cells together. Only 30–50% of patients who meet the
new Task Force Criteria for ARVC18 will have an identified
genetic desmosomal abnormality.19,20 This figure is higher
if there is a family history of the disease. Importantly, the
Marcus and Abidov ARVC 2012
absence of a desmosomal genetic abnormality does not exclude the disease. Commercial genetic testing can be used
to identify family members who may or may not be symptomatic and who have a similar genetic desmosomal abnormality as the proband. The family member who has the
genetic abnormality is generally advised to avoid engaging
in competitive sports because this is known to facilitate the
onset or progression of the disease.21 However, the individual
who has the familial genetic defect may not have any clinical
manifestations and have a normal life expectancy without
developing the disease. Thus the genetic–phenotypic relationship is quite variable. Note that 5–20% of patients with
the diagnosis of ARVC may have 2 genetic abnormalities
either located on the same protein such as plakophilin or on
another desmosomal protein.22 Individuals with 2 desmosomal genetic defects have a greater chance of having phenotypic expression of the disease and are often more severely
affected.23 Interpretation of genetic abnormalities is complicated by the fact that up to 16% of normal controls may
have a desmosomal genetic abnormality. Therefore the interpretation of a genetic abnormality must be done with great
caution, and genetic counseling is recommended.
3
Figure 2. Cardiac MRI image demonstrating dilatation of the RVOT with
focal bulging anteriorly (arrow) in a patient with ARVC. Reproduced with
permission from Tandri H, Bomma C, Calkins H, Bluemke DA. J Magn
Reson Imaging 2004;19:848-858.
Imaging in ARVC
In patients who are suspected of having RV cardiomyopathy, cardiac imaging studies usually reveal an enlarged right
ventricle with focal wall motion abnormalities. Normal RV
function may be misinterpreted as consistent with general or
local hypokinesis resulting in overdiagnosis.24 Recognition
of this fact has resulted in modification of the guidelines for
the diagnosis of this disease.18 To meet imaging criteria for
ARVC the new Task Force Guidelines include a combination
of decreased RV function as well as definite RV wall motion
abnormalities.
Imaging modalities to evaluate RV structure and function in patients suspected of ARVC include 2-D echocardiography, cardiac magnetic resonance (CMR) imaging, cardiac computed tomography (CT) and angiography.25,26 When
these studies are performed, it is important that the technician focuses on imaging the RV rather than on the LV and
this should be clearly stated in the imaging request from the
referring physician. Suggested protocols for 2-D echocardiography and CMR are available on www.arvd.org. Experience
with variability in interpretation of imaging studies including the CMR indicates that at least 2 imaging modalities
should be performed to confirm if there is an RV imaging
abnormality.
The new Task Force Criteria18 require both a decrease in
RV function as well as an RV wall motion abnormality that
is more pronounced than “hypokinesis.” This latter term that
was used in the previous Task Force Criteria was not included
in the new Task Force Criteria because of large interobserver
variability. By echocardiography, it has been found that the
RV outflow tract is the most commonly enlarged dimension
in ARVC probands.27 Guidelines for the echocardiographic
assessment of the right heart has recently been published.28
The most important features of the CMR are that it permits
reproducible and standardized quantification of RV volumes
and ejection fraction (Fig. 2). Dynamic images of the RV in
multiple views can be obtained by cine images using a steady
state free precision sequence. Nevertheless, interpretation of
Figure 3. Cardiac CT of a 16-year-old male with ARVC. Fibrofatty infiltration and a free RV wall aneurysm (arrow) are seen.
the CMR images, particularly the presence of intramyocardial fat/wall thinning can be misinterpreted.24
CMR cannot be used in some patients because of highly
irregular or fast heart rates, claustrophobia, clinically unstable patients, or the presence of a pacemaker or ICD. Under
these circumstances, CT scanning is an imaging alternative.
CT scanning is not a routinely used technique for RV assessment because of significant radiation exposure and the
need to use contrast.29 Modern CT scanners can now acquire
data with less radiation. In comparison with CMR, CT has
a lower temporal resolution and tends to overestimate end
systolic and end diastolic volumes.26 CT can show the presence of regional dysfunction with an accuracy comparable to
CMR (Fig. 3).
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Journal of Cardiovascular Electrophysiology
Vol. No.
Risk Stratification and Treatment
Risk stratification is imperfect. Patients who have documented or even borderline criteria for ARVC are usually
treated with ICD’s. In the North American ARVC Registry
77% of newly diagnosed probands or affected family members received this therapy.19 Although it is well documented
from other studies that the majority of probands who had
ICDs will have appropriate antitachycardia pacing or shock
therapy for VT or ventricular fibrillation, the actual number
of lives saved by this approach may be greatly exaggerated.
This is because most patients with ARVC have normal LV
function and can tolerate sustained VT at rates over 200
beats/minute without syncope or death. Risk factors for ICD
therapy in patients with ARVC include a history of aborted
sudden death, syncope, young age, decreased LV function,
and a marked decrease in RV function.30 In contrast, family members who have the genetic defect with no clinical
manifestations of the disease are at minimal risk and should
not receive a defibrillator. A major uncertainty with regard to
proper therapy is the young person with ARVC who has frequent PVCs or a history of well-tolerated VT. Implantation of
an ICD in these young patients is not without risk because of
the long anticipated duration of life with an ICD that can be
associated with complications including lead malfunction or
ICD pocket or lead infection. A recently introduced ICD that
has only subcutaneous lead may be a preferable alternative
therapy, but is yet unproven.
A promising approach to therapy for patients with sustained monomorphic VT is catheter ablation. The results of
endocardial ablation to prevent arrhythmia occurrence have
been disappointing because of the high rate of recurrence of
VT. Nevertheless, the recent recognition that the epicardial
scar is usually much more extensive then the endocardial area
of involvement has resulted in evolution of ablation strategies to involve both the epicardium and the endocardium.
Preliminary results are encouraging with success rates of
85% at 3 years.31 Epicardial ablation is not without hazard because of myocardial perforation, tamponade, etc., and
should be done in selected centers that have considerable
experience with this approach.32
Antiarrhythmic drug therapy to prevent recurrent sustained VT has not been extensively studied except in one
relatively small series of patients treated with sotalol and
evaluated by electrophysiological studies. Other drugs that
have been reported to be effective include amiodarone33,34
alone or beta-blocking drugs in conjunction with type 1C
drugs such as flecainide.
Prevention of the phenotypic expression of the disease,
especially with family members with desmosomal abnormalities, needs to be evaluated. There are suggestions from
experimental data in knockout ARVC mice that vasodilator
drugs such as isosorbide may decrease the progression of
RV enlargement.35 In addition, excessive exercise appears to
exacerbate the manifestations in the disease in experimental
animals. The preventive approach of treating family members with genetic ARVC defects using beta-blockers or ACE
inhibitors is reasonable but there are no clinical supportive
data. Prevention of RV dilatation should be a fruitful area of
research. Research in ARVC is now focusing on understanding the genetics and molecular basis of the disease.
In summary, the diagnosis of ARVC can often be suspected on the basis of ECG abnormalities. It is difficult to
accurately interpret imaging studies of the right ventricle
because of its irregular structure and lack of symmetrical
pattern of contracture. Commercial genetic testing is available but the results must be interpreted with caution because
only 30–50% of patients with ARVC have an identifiable
genetic abnormality and individual patients may have more
than one desmosomal defect. Risk stratification is imperfect, but it is clear that high-risk patents should be treated
with an ICD. Improved methods of catheter ablation are
promising.
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