A Young Male with Arrhythmogenic Right Ventricular

Dysplasia : a case report

Background
Arrhytmogenic Cardiomyopathy (ACM) is a genetically determined cardiomyopathy
characterized by fibrofatty replacement of the myocardium.1.2.3 Formerly called “arrhythmogenic right
ventricular dysplasia / cardiomyopathy,”1,2 it is better termed ACM because it is now recognized that
biventricular involvement occurs in up to 50% of cases and that a small proportion of cases affect
predominantly the left ventricle.1 Arrhythmogenic right ventricular cardiomyopathy (ARVC), also
known as arrhythmogenic rightventricular dysplasia, is an inherited cardiomyopathy associated with
arrhythmia, heart failure, andsudden cardiac death (SCD). Considerable strides have been made in
understanding the pathogenesis, genetics, and diagnosis of ARVC, since it was first described over 20
years ago.
ACM is the most arrhythmogenic form of human heart disease and a major cause of sudden
death in young. 2

The disorder is conceptualized as having three stages: an early subclinical phase in which
imaging studies are negative but during which sudden cardiac death can still occur; next , a phase in
which (usually) right ventricular (RV) abnormalities are obvious without any clinical manifestation of
RV dysfunction but with the development of symptomatic ventricular arrhythmia; and finally ,
progressive fibrofatty replacement and infiltration of the myocardium leading to severe RV dilatation
and aneursym formation and associated right-sided heart failure. LV dilatation and failure may also
arise this stage or may occur later (sometimes referred to as phase 4).1

The electrical manifestations of ACM are a reflection of the pathologic disturbance. In the
early stage, slow conduction and electrical uncoupling may lead to a fatal arrhytmia . As the disease
progresses, fibrofatty infiltration results in inhomogeneous activation and a further delay in
conduction. The predominant site of RV involvement is often the “triangle of dysplasia,” an area
involving the RV outflow tract, an area below the tricuspid valve, and the RV apex; this is the most
common area of RV thinning, regional dilatation, and aneurysm formation. This anatomic area and its
abnormalities in the ACM are responsible for the typical ECG appearance during sinus rhythm and a
typical monomorphic ventricular tachycardia (VT) characterized by left bundle branch block
morphology with a superior axis.

An intriguing postulate to explain the progressive nature of ACM and the predilection for the
pathology to affect the right ventricle comes from the observation that the prevalence of sudden
cardiac death may be higher in athletes with ACM than in sedentary patients. This has led to the
hypothesis that the right ventricle, being thinner than the left ventricle, is more susceptible to
mechanical stretch, particularly during exercise.1,3 Mechanotransduction, or conversion of mechanical
stimuli to biochemical intracellular signals, may further increase dysfunction at the cellular level.

Discussion

Genomic Cause of Arrhythmogenic Cardiomyopathy

Unlike genetic DCM, which has a final common phenotype despite its extensive locus
heterogeneity, ACM is driven by molecular genetic alterations in genes encoding proteins that are key
for cell to cell adhesion. Extensive work over the past decade has implicated genes encoding the
desmosome, one of three key components of the intercalated disc, the end-to-end connection between
ventricular myocytes in the pathogenesis of ACM.1,4 In addition to desmosomes, the intercalated disc
includes gap junctions mediating small-molecule communication. Mechanical coupling is mediated
through the desmosome and adherens junctions, and disruptions of desmosomal proteins have been
asscoiated with ACM. The mutant desmosomes also cause remodelling of gap junctions explain how
electrocardiographic changes and ventricular arrhythmias can develop before the loss of myocytes and
dysfunction of the right ventricle become apparent ( the concealed phase of disease).4

The classic hallmark of ACM, fibrofatty replacement, is now understood to be related to

aberrant Wnt signaling of desmosomal proteins, as well as direct plakoglobin signalling, which
transforms myocytes into adipocytes with disease progression.1,5 Plakoglobin signal level were
reduced not only in right ventricular regions showing typical pathological changes of fibrofatty
replacement but also in normal-appearing left ventricle and interventricular septum, including the
subendocardium in these areas.5

Mutation in five genes that encode desmosomal proteins (desmoplakin, plakoglobin,

plakophilin 2, desmoglein 2, and desmocollin 2) have been found in ACM and in two related
autosomal recessive disorder, Naxos disease ( ACM accompinied by woolly hair and palmoplantar
keratorderma) and the Carjaval syndrome (which has similar dermatologic phenotype but in which
left ventricular involvement is predominant). Two other, nondesmosomal genes have been implied in
ACM: one for transforming growth factor β3 (TGF β3) and the other for transmembrane protein 43
(TMEM43).4

Clinical Presentation

Generally, ARVC has a predilection for males who typically present prior to age 40. The
diagnosis should be considered in young patients with syncope due to ventricular tachycardia (VT),
cardiac arrest, or adult patients with congestive heart failure.16 While 30%-50% of ARVC cases are
familial, incomplete penetrance results in variable disease manifestations; thus a wide disease
spectrum is present. Classically, 4 phases of ARVC have been described.17
• The silent phase is associated with minimal symptoms, infrequent ventricular premature
beats or tachycardia, and minimal changes on noninvasive imaging.
• The self-evident phase is characterized by the presence of sustained VT as well as structural
abnormalities involving the RV.
• The right ventricular phase is characterized by the development of progressive dilation and
loss of RV contractility.
• The development of biventricular heart failure occurs due to the progressive involvement of
the left and right ventricles.

Arrhythmias are of left bundle branch block (LBBB) morphology, reflecting their genesis
within the RV. Patients may present with frequent ventricular premature beats, sustained VT, or
cardiac arrest. VT, which is most commonly due to macro reentry circuits involving islands of
fibrofatty tissue, is frequently precipitated by an increase in sympathetic tone. Heart failure symptoms
(predominantly isolated RV failure) may also develop in individuals with ARVC, typically in the 4th
and 5th decades of life.1 ARVC is one of a few myocardial diseases that results in RV failure in the
absence of pulmonary hypertension. Right heart failure often presents within 4 to 8 years after the
development of a complete right bundle branch block (RBBB).18 Patients may present with
biventricular failure. Left-sided heart failure is often due to progressive fibrofatty replacement of the
LV. Patients presenting with biventricular failure may be inappropriately diagnosed with dilated
cardiomyopathy. Distinguishing between dilated cardiomyopathy and ARVC is important because
patients with ARVC are more prone to arrhythmic events.8.9.10

Diagnosis

The more advanced the disease, the easier the diagnosis, but recognition of earlier stages,
which may be manifested as aborted sudden death without detectable structural abnormalities, can be
difficult. In addition, with increasing use of cardiac MRI for the diagnosis of cardiac pathology, a
trend toward overdiagnosis of ACM is now being recognized. This often occurs because a normal
variant of fatty infiltration of the right ventricle is misinterpreted as ACM whereas in true ACM a
combination of fatty infiltration and fibrous replacement is present rather than isolated fatty
infiltration.

The diagnosis of ACM currently rests on the combination of clinical, electrocardiographic,

and genetic findings, which are divided into “major” and “minor” diagnostic criteria as proposed in a
2010 revision of the original 1994 diagnostic criteria.
 Table 1. Diagnosis Criteria of ARVC8

ECG parameter are featured prominently in the 2010 diagnostic criteria. Previously, only the
occurrence of epsilon waves and prolongation of the QRS (>100miliseconds) in V 1 to V3 were
considered major criteria, whereas inverted T waves in the right precordial leads, late potentials on the
signal-averaged ECG, left bunbdle-branch block-type ventricular tachycardia, and frequent (>1000
per 24 hours) ventricular extrasystloes were minor criteria. Epsilon waves, representing delay in
depolarization of the right ventricular free wall and outflow tract, are highly specific for ACM, and
have been observed to occur during VT. However, like many of the 1994 diagnostic criteria, epsilon
waves occur in only a minority of patients with disease. To maintain specificity but enhance but
enhance sensitivity, specific quantitative abnormalities in repolarization and conduction and specific
types of arrhythmias are now categorized as major and minor criteria, and in many cases, thresholds
have been reduced (eg, >500 extrasystoles is now a minor criterion)2

Figure 1. Typical ECG of a patient with ARVC

 ACM is commonly associated with nonsutained or sustained VT. The VT in this condition
has a LBBB morphology, reflecting its origin from the right ventricle. During sinus rhythm anterior
precordial T wave inversion are commonly present. 6

Cardiac Biopsy

Endomyocardial biopsy for ACM is one of the diagnostic criteria but should be undertaken with great
caution because of the potential both for higher major complication rates and for false negative
findings. Because the septum is uncommonly involved in ACM, RV septal biopsy may lead to a false-
negative diagnosis. On the other hand, RV free wall biopsy carries a significantly higher risk for
cardiac perforation, particularly if pathologic thinning is present. In the early stages of the disease,
with arrhytmia but little overt structural change, findings on biopsy speciments may also be negative.

Approach to Clinical Genetic Evaluation, Including Clinical Genetic Testing

Current studies estimate that a plausible genetic cause can be identified in approximately half of ACM
cases. The impact of multiple mutations in desmosomal genes has been emphasized, as well as the
impact of the revised task force clinical criteria, which has increased the sensitivity of molecular
genetic testing. The current literature is limited by molecular genetic testing driven by the phenotype
classified as ACM, so the frequency of a plausible genetic cause identified in individiuals or families
categorized as having idiopathic or familial DCM has not been systematically evaluated by for testing
ACM genes. For clear-cut cases of ACM, genetic testing is indicated so that cascade testing of at-risk
family members can be accomplished. This is particularly relevant for ACM insofar as
arrhythmias,especially sudden cardiac death, can occur before other phenotypic features become
evident. The genes involved in ACM show significant allelic heterogeneity, thus making it difficult to
discern pathogenic variants from uncommon polymorphisms, as is the case for clinical genetic testing
for all cardiomyopathies. Pancardiomyopathy testing, especially for a phenotype of prominent VT,
ventricular fibrillation, or sudden cardiac death with biventricular dilatation and systolic dysfunction
of unknown cause otherwise concistent with DCM, may also yield rare variants in the genes
associated with ACM. Even though conventional recommendations currently discourage the use of
genetic testing for the diagnosis of ACM, molecular geneting testing will probably be used more
frequently in the near future to assist in makin the diagnosis of ACM, especially as genetic testing
proliferates and is used more commonly for all cardiomyopathies regardless of phenotype.

Differential Diagnosis

The differential diagnosis of ACM in the early diagnosis of ACM in the early stages (before the onset
of visible structural abnormalities) includes idiopathic and RV outflow tract VTs. The morphology of
the classic ACM-related VT differs from these entities, and in the presence of precordial T wave
inversion during sinus rhythm, ACM should be the initial diagnosis. Cardiac sarcoidosis may
occasionally mimic ACM morphologically and be indistinguishable, even with mulriple imaging
modalities. Cardiac biopsy in patients with sarcoidosis often fails to show pathognomonic granulomas
but may reveal extensive fibrosis, which may also be confused with ACM.

Treatment

Currently, the mainstay of theraphy for ACM is suppression and prevention of ventricular arrhythmias
and the risk for sudden cardiac death. Antiarrhytmic drugs are often unsuccessful in completely
abolishing the arrhtmias. The classic monomorphic VT in ACM with predominant RV involvement is
generally well tolerated, even at a rapid rate, possibly because of preserved LV function in most
patients. Neverthless, VT of a different morphology may occur and sudden death is not uncommon.
Beta blockers have not been shown to be of value in treating the usual VT of ACM. Accordingly, an
implantable defibrillator is recommended in patients with aborted sudden death, syncope, or
decreased LV function. In well-tolerated monomorphic VT, catheter ablation of the VT is an option.
Ablation appears to be most successful when lesions are made in both the epicardial and endocardial
surfaces of the heart and should be performed only at centers experienced in the technique. Cathether
ablation is associated with greater than 85% arrhythmia-free survival rate at 3 years, with VT
recurrence being well tolerated in most of the remaining patients. Based on the theory that mechanical
stress is a trigger for disease progression, as well as evidence in plakoglobin-deficient mice that
pharmacotherapeutic load reduction slows progression of the disease, the use of ACE inhibitors
and/or nitrates has been suggested, although no clinical trial evidence is available to support such
treatment. 9,10

Conclusion

ARVC is a rare, progressive cardiomyopathy associated with ventricular arrhythmias and

heart failure. The disease should be suspected if phycisian have a patient with unexplained causes of
ventricular arryhtmias and right heart failure. Treatment is aimed mainly at the prevention and
management of malignant arrhythmias and sudden death.

References
1. Falk RH, Hershberger RE. The dikated, Restrictive, and Infiltrative Cardiomyopathies. In:
Braunwald’s Heart Disease, A Textbook of Cardiovascular Medicine.10th ed. Philadelphia:
Elsevier Saunders; 2015; p 1557-60.
2. Saffitz JA. Arrhytmogenic Cardiomyopathy : Advances in Diagnosis and Disease
Pathogenesis. Circulation. 2011;124:e390-e392.
3. Engelstein ED, Zipes DP. Sudden Cardiac Death. In : Hurst’s The Heart Arteries and Veins
Companion Handbook. 9th ed. New York: McGraw-Hill;1999; p 97.
4. Watkins H, Ashrafian H, Phil D, Redwood C. Inherited Cardiomyopathies. N Eng J Med.
2011;364: 1643-56.
5. Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, et al. A new Diagnostic
Test for Arrhytmogenic Right Ventricular Cardiomyopathy. N Eng J Med. 2009; 360: 1075-
84.
6. Chakko S, Myerburg RJ. Arrhythmias and Conduction Disturbances. In : Hurst’s The Heart
Arteries and Veins Companion Handbook. 9th ed. New York: McGraw-Hill;1999; p 45-6.
7. Abramson BL, Hesayen AA, Casella L, Charron T, Cheema A, et all. Arrythmogenic right
ventricular cardiomyopaty-not just a matter of fat. Cardiology Rounds: Vol XI; 2006.
8. Avramides D, Protonotorios N, Asimaki A, Matsakas E. Arrhtmogenic Right Ventricular
Cardiomyopathy. Hellenic J Cardiol 2011.
9. Corrado D, Basso C, Thiene G. Cardiomyopathy: Arrhythmogenic right ventricular
cardiomyopathy: diagnosis, presentation and treatment. Heart 2000;83: 588-95.
10. Basso C, Thiene G. Adipositas cordis, fatty infiltration of the right ventricle, and
arrhythmogenic right ventricular cardiomyopathy. Just a matter of fat?
Cardiovasc Pathol 2005;14:37-41.