A study investigating Arrhythmogenic right ventricular dysplasia/cardiomyopathy

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Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a rare heritable heart muscle disorder. Its prevalence has been estimated to be approximately 1 in 5000 individuals, with incidence more common in men. ARVD/C is one of the major causes of sudden death particularly in the young and athletes. It was estimated that up to 20% of sudden deaths in the young are accounted for previously undiagnosed ARVD; the fact that strongly implicates the disease to juvenile death. The major cause of ARVD in 50% of symptomatic individuals is mutation in genes encoding cardiac desmosomal proteins. However, other gene modifiers and environmental factors seem to contribute to the disease etiology. Although the ARVD is associated with right ventricle abnormalities, researchers had found equal right and left ventricle involvement in the disease.


Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a progressive cardiomyopathy, characterized by replacement of myocardium of the right ventricle wall with fibro-fatty tissue. This in turn results in right ventricular dilation and contractility dysfunction. Life threatening arrhythmias and sudden cardiac death also occur, because this fibro-fatty tissue causes electrical instability of the right ventricular wall. ARVD/C is familial, and the mode of inheritance in most cases is autosomal dominant with low penetrance and variable expressivity. However, the recessive form of the disease is known as Naxos disease; the case in which the ARVD/C is associated with wooly hair and keratoderma. Although the prevalence of the disease was estimated to be approximately 0.02% in general populations, it is dependent on geographic circumstances. In certain regions of Italy and Greece (Island of Naxos) the prevalence reaches 0.4% to 0.8%.

In 1736, Giovanni Maria Lancisi was the first to describe ARVD in his book De Motu Cordis et Aneurysmatibus. He wrote about occurrence of a disease in four generations of a certain family, with the affected individuals suffered from palpitations, heart failure, dilation of the right ventricle (RV) and sudden death. Dalla Volta et. al., in 1973, observed a case with auricularization of the RV pressure curve (i.e. RV behaves like an atrium). A biopsy from such patient revealed the presence of fibrosis in the myocytes of the RV.

Nevertheless, the name ARVD was not introduced until 1978, when Frank and Fontaine defined the disease as "total or partial replacement of right ventricular muscle by adipose and fibrous tissue accociated with arrhythmias". In 1988, series of sudden deaths in the young (≤35 years) was observed, with pathology characterizing ARVD/C, occurs mostly during exerting effort. The World Health organization, in 1995, classified ARVD as a cardiomyopathy.

The possible underlying mechanisms of AVRD/C

Several theories were proposed concerning the mechanism of the disease. These theories tried to find the relation between the mutations in cardiac desmosome genes and the clinical features appearing, which are RV enlargement and dysfunction, and fibrofatty tissue formation. The simplest theory assumes that the loss of myocyte adhesion leads to cell death and regional fibrosis. The RV fibro-fatty tissue, in turn, would result in arrhythmia which usually accompanies ARVD/C. The RV is more susceptible to the disease than the left owing to its thinner walls and its normal dilatory response to the exercise. This theory or model is purely structural, in which environmental factors as exercise or inflammation increase the impaired cell adhesions and accelerate disease progression.

Another model, that is more complex, involves the canonical Wnt/β-catenin signaling pathway, which inhibits adipogenesis through stopping the differentiation of mesodermal precursors into adipocytes. Plakoglobin is a protein having the ability to localize to plasma membrane and nucleus. It was found that plakoglobin is freed and translocated to the nucleus when the desmoplakin is disrupted. In the nucleus, plakoglobin suppresses the canonical Wnt/β-catenin signaling. Therefore, differentiation of adipose tissue occurs in the myocardium of ARVD/C patients.

Apoptosis of cardiomyocytes seems to contribute to the cell loss observed in ARVD/C. the analysis of ARVD biopsies from myocardial tissue revealed an increased DNA fragmentation, a characteristic feature of apoptotic cell. Recent studies found that plakoglobin increases the expression of two apoptotic genes, and that Wnt/β-catenin signaling pathway control the apoptotic response in preadipocytes.

Clinical features in ARVD/C

1) Subclinical phase with concealed structural abnormalities, where the diseased person presents no symptoms and the heart arrest may be the only manifestation of the disease.

2) Overt electrical disorder, accompanied by syncope and palpitations. The most typical symptom of the disease is ventricular arrhythmias originated from RV.

3) RV failure, since the progressive myocardium loss in RV impairs the mechanical function and eventually causes severe pump failure.

4) Biventricular failure, in which the ventricular septum and LV are involved in the disease. In this case heart failure and contractile dysfunction occur, and heart transplantation may be required.

Sudden cardiac death can be the first presentation of the disease. Generally, the risk for sudden death due to ARVD/C increases in:

Younger patients

Patients who have recurrent syncope

Patients with LV involvement

Patients with a previous history of cardiac arrest

The molecular aspects in ARVD/C

ARVD/C is a cell-cell adhesion disease; since a number of genetic studies have identified mutations occurring in genes encoding cardiac desmosomal proteins. Desmosomes support the structural and functional activity of cardiac tissue. Desmosomes involve five major proteins; plakoglobin, plakophilin2 and desmoplakin that attach desmin intermediate filaments to cadherins, supporting the cell-cell mechanical adhesion. Desmoglein and desmocollin (cadherins) form an extracellular zipper-like dimer with those of cadherins in adjacent cardiac myoctes, since they are transmembrane proteins. The mutation in a gene encoding one of these desmosomal proteins was found to contribute to AVRD/C onset.

1) Plakoglobin mutation

The deletion of two base pairs of the plakoglobin gene produces a C-teminal truncated protein and causes the autosomal recessive form of ARVD/C, Naxos disease, characterized by hair and skin abnormalities. Therefore, the recessive ARVD/C is predictable from early infancy owing to the wooly hair and cutaneous abnormalities observed in the child. In Naxos disease, the RV abnormalities is involved and progresses with time.

2) Plakophilin-2 mutation

Plakophilin-2 gene mutation is known to be the most common cause of ARVD/C. Most of plakophilin mutations are detected in the C-terminal half of the protein molecule. The observed phenotype is the fibrofatty replacement in the RV myocardium. The incidence of plakophilin mutation is greater than that of plakoglobin, due to the ability of the latter to be compensated by other desmosomal adhesion protein.

3) Desmoplakin mutation

There are five dominant and two recessive mutations reported in desmoplakin protein; they truncate either N or C-terminal of the protein. In case of N-terminal truncated desmoplakin (especially at the plakoglobin binding site), the phenotype observed is typical to ARVD/C in the electrocardigraphic and structural abnormalities. The mutations causing C-terminal truncation exhibit broader cardiac phenotype with LV involvement.

4) Desmoglein-2 mutations

There are four isoforms of desmoglein family each with a separate gene. Desmoglein-2 is the most expressed gene in the cardiac tissue, so it is strongly associated with ARVD etiology. Most of the mutations occurring in desmoglein-2 are missense.

5) Desmocollin-2 mutations

Only five desmocollin-2 mutations are reported. They are less frequent in ARVD/C.

Genetic analysis of ARVD/C

The genomic DNA is extracted from blood samples, and amplified with PCR using specific primers flanking the target desmosomal gene(s) associated with the disorder. PCR products are resolved and analyzed on agarose gel electrophoresis before sequencing.

Treatment of ARVD

The management and treatment of patients with ARVD is classified into two groups, the conservative and non-conservative group. The conservative group principally aims to symptomatic relief and delaying RV or biventricular dysfunction as much as possible. This can be achieved by using the standard heart failure therapy including anticoagulants. Another important goal of conservative therapy is suppression of ventricular arrhythmias. Patients with non life-threatening ventricular tachycardia (VT) can be conservatively treated with antiarrhythmic drugs. Sotalol was found to be the most effective antiarrhythmic drug with an efficacy rate of 68%. Amiodarone antiarrhythmic is used as well, having a 15% efficacy rate.

The non conservative group involves the treatment with radiofrequency ablation, Implantable Cardioverter Defibrillator (ICD) or surgery. First, radiofrequency ablation is used when the ARVD patient - who have well tolerated and non life threatening VT - is unresponsive or intolerant to antiarrhythmic drugs. Second, Implantable Cardioverter Defibrillator is life-saving for ARVD/C patients at high risk for sudden cardiac death. This includes patients who exhibit incomplete suppression of arrhythmia or intolerance using the antiarrhythmic drug therapy, and patients who had unstable VT. However, there are two main risks when applying ICD:

Myocardial perforation during implantation of the RV leads may occur owing to the RV wall thinning

Since ARVD/C is progressive, the RV infiltration continuously occurs resulting in ICD malfunction

Third, ARVD/C patients can be treated surgically. The surgery decreases the lethal effect of cardiac arrhythmia through disconnecting the RV wall. Such disconnection prevents the VT from spreading to the LV, and decreases the ventricular mass available to fibrosis, since it isolate the RV from the left one.